SMART MODE:

NORMAL GENOMIC

• Phakdeekitcharoen B, Watnick TJ, Germino GG
• Mutation analysis of the entire replicated portion of PKD1 using genomic DNA samples.
• J Am Soc Nephrol. 2001; 12: 955-63
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• The replicated portion of PKD1, which comprises nearly 70% of the length of the gene, is predicted to harbor at least 85% of the mutations present in affected autosomal dominant polycystic kidney disease type 1 pedigrees. The relative paucity of reported mutations involving this segment is attributable to the significant technical challenges posed by the genomic structure of the gene. Previous genomic DNA-based strategies were unable to evaluate exons 1 and 22 and relied on the use of 10- to 13-kb PCR products. In this report, a set of six novel primer pair combinations, which can be used with previously reported reagents to analyze all of the exons in the replicated region (exons 1 to 34), are described. No product is greater than 5.8 kb in length, and various primer combinations can be used to reduce this length in half. Using this approach, two new pathogenic mutations, four novel disease-associated missense substitutions, and six new normal variants were identified. These new reagents should prove useful to investigators interested in performing DNA testing for this disorder.

• Vandorpe DH et al.
• The cytoplasmic C-terminal fragment of polycystin-1 regulates a Ca2+-permeable cation channel.
• J Biol Chem. 2001; 276: 4093-101
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• The cytoplasmic C-terminal portion of the polycystin-1 polypeptide (PKD1(1-226)) regulates several important cell signaling pathways, and its deletion suffices to cause autosomal dominant polycystic kidney disease. However, a functional link between PKD1 and the ion transport processes required to drive renal cyst enlargement has remained elusive. We report here that expression at the Xenopus oocyte surface of a transmembrane fusion protein encoding the C-terminal portion of the PKD1 cytoplasmic tail, PKD1(115-226), but not the N-terminal portion, induced a large, Ca(2+)-permeable cation current, which shifted oocyte reversal potential (E(rev)) by +33 mV. Whole cell currents were sensitive to inhibition by La(3+), Gd(3+), and Zn(2+), and partially inhibited by SKF96365 and amiloride. Currents were not activated by bath hypertonicity, but were inhibited by acid pH. Outside-out patches pulled from PKD1(115-226)-expressing oocytes exhibited a 5.1-fold increased NP(o) of endogenous 20-picosiemens cation channels of linear conductance. PKD1(115-226)-injected oocytes also exhibited elevated NP(o) of unitary calcium currents in outside-out and cell-attached patches, and elevated calcium permeability documented by fluorescence ratio and (45)Ca(2+) flux experiments. Both Ca(2+) conductance and influx were inhibited by La(3+). Mutation of candidate phosphorylation sites within PKD1(115-226) abolished the cation current. We conclude that the C-terminal cytoplasmic tail of PKD1 up-regulates inward current that includes a major contribution from Ca(2+)-permeable nonspecific cation channels. Dysregulation of these or similar channels in autosomal dominant polycystic kidney disease may contribute to cyst formation or expansion.

• Weston BS, Bagneris C, Price RG, Stirling JL
• The polycystin-1 C-type lectin domain binds carbohydrate in a calcium-dependent manner, and interacts with extracellular matrix proteins in vitro.
• Biochim Biophys Acta. 2001; 1536: 161-76
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• Mutations in the PKD1 gene are responsible for 85% of cases of autosomal dominant polycystic kidney disease (ADPKD). This gene encodes a large membrane associated glycoprotein, polycystin-1, which is predicted to contain a number of extracellular protein motifs, including a C-type lectin domain between amino acids 403--532. We have cloned and expressed the PKD1 C-type lectin domain, and have demonstrated that it binds carbohydrate matrices in vitro, and that Ca(2+) is required for this interaction. This domain also binds to collagens type I, II and IV in vitro. This binding is greatly enhanced in the presence of Ca(2+) and can be inhibited by soluble carbohydrates such as 2-deoxyglucose and dextran. These results suggest that polycystin-1 may be involved in protein-carbohydrate interactions in vivo. The data presented indicate that there may a direct interaction between the PKD1 gene product and an ubiquitous extracellular matrix (ECM) protein.

• Bouba I et al.
• Novel PKD1 deletions and missense variants in a cohort of Hellenic polycystic kidney disease families.
• Eur J Hum Genet. 2001; 9: 677-84
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• The autosomal dominant form of polycystic kidney disease is a very frequent genetically heterogeneous inherited condition affecting approximately 1 : 1000 individuals of the Caucasian population. The main symptom is the formation of fluid-filled cysts in the kidneys, which grow progressively in size and number with age, and leading to end-stage renal failure in approximately 50% of patients by age 60. About 85% of cases are caused by mutations in the PKD1 gene on chromosome 16p13.3, which encodes for polycystin-1, a membranous glycoprotein with 4302 amino acids and multiple domains. Mutation detection is still a challenge owing to various sequence characteristics that prevent easy PCR amplification and sequencing. Here we attempted a systematic screening of part of the duplicated region of the gene in a large cohort of 53 Hellenic families with the use of single-strand conformation polymorphism analysis of exons 16-34. Our analysis revealed eight most probably disease causing mutations, five deletions and three single amino acid substitutions, in the REJ domain of the protein. In one family, a 3-bp and an 8-bp deletion in exons 20 and 21 respectively, were co-inherited on the same PKD1 chromosome, causing disease in the mother and three sons. Interestingly we did not find any termination codon defects, so common in the unique part of the PKD1 gene. In the same cohort we identified 11 polymorphic sequence variants, four of which resulted in amino acid variations. This supports the notion that the PKD1 gene may be prone to mutagenesis, justifying the relatively high prevalence of polycystic kidney disease.

• Torra R et al.
• [Mutational analysis of the PKD1 and PKD2 (type 1 and 2 dominant autosomal polycystic kidney) genes]
• Nefrologia. 2000; 20: 39-46
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• Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. It is caused by mutations in at least two different genes: PKD1 and PKD2. The study of mutations in these genes is very difficult nowadays. In this study we have analyzed the non reiterated region of the PKD1 gene and all the exons and intron exon boundaries of the PKD2 gene. The technique used to study these genes have been single strand conformation analysis and heteroduplex. We have found 25 differences within the DNA sequence of the PKD1 gene with respect to the published sequence. Seven of these changes correspond to nonsense, missense, frameshifting and splicing mutations. The rest of changes correspond to polymorphisms or rare DNA variants. In the PKD2 gene we have identified 8 new mutations and one polymorphism. Six of these mutations are frameshifting, one is missense and the other one is a large deletion of the PKD2 gene. The rate of mutation detection within the PKD1 gene has been 4% and the rate for PKD2 has been 100%. We have not observed any correlation between genotype and phenotype either in the PKD1 nor in the PKD2 gene. The mutation analysis of ADPKD genes is very difficult, specially for the PKD1 gene. The rate of mutation detection is higher in the PKD2 gene but the global efficacy of the technique is very low as PKD2 represents only 15% of ADPKD patients. Nowadays linkage analysis is still the most useful technique for the molecular diagnosis of ADPKD patients.

• Trudel M, Guillaume R
• Progress in molecular genetics of autosomal dominant polycystic kidney disease.
• Front Biosci. 2000; 5: 31220-31220
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• Among the prevalent human genetic disorders, human autosomal dominant polycystic kidney disease is certainly one of the most challenging, both from a clinical and a fundamental perspective. In the recent years, important progress opened novel research avenues to elucidate the genetic basis, the cellular pathophysiologic mechanisms and the molecular function of genes and proteins involved in autosomal dominant polycystic kidney disease.

• Thongnoppakhun A, Rungroj N, Wilairat P, Vareesangthip K, Sirinavin C, Yenchitsomanus PT
• A novel splice-acceptor site mutation (IVS13-2A>T) of polycystic kidney disease 1 (PKD1) gene resulting in an RNA processing defect with a 74-nucleotide deletion in exon 14 of the mRNA transcript.
• Hum Mutat. 2000; 15: 115-115
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• Autosomal dominant polycystic kidney disease (ADPKD) occurs mainly from mutations of polycystic kidney disease 1 (PKD1) gene. A novel mutation of the PKD1 gene due to a nucleotide substitution in splice-acceptor site of IVS13 (AG->TG) was identified by analyses of PKD1-cDNA and genomic DNA. The IVS13-2A>T substitution resulted in an inactivation of this splice site and utilization of cryptic splice acceptor site in exon 14, causing a 74-nucleotide deletion of this exon in the PKD1-mRNA transcript. The abnormal transcript was present ectopically in the patients' lymphocytes. The partial deletion of PKD1-mRNA leads to frameshift translation and introduces a termination signal at codon 1075. The truncated protein with about one quarter of the full-length polycystin-1 is most likely inactive. Thus, the effect of this mutation would be "loss-of-function" type. Allele specific amplification (ASA) was developed to detect the mutation in DNA samples of other family members. The mutation was present in 11 affected but absent in 13 unaffected family members, corresponding to the results of linkage analysis. In addition, it was not observed in DNA samples of 57 unrelated healthy individuals. Hum Mutat 15:115, 2000.

• Bogdanova N et al.
• Screening the 3' region of the polycystic kidney disease 1 (PKD1) gene in 41 Bulgarian and Australian kindreds reveals a prevalence of protein truncating mutations.
• Hum Mutat. 2000; 16: 166-74
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• Screening for disease-causing mutations in the unique region of the polycystic kidney disease 1 (PKD1) gene was performed in 41 unrelated individuals with autosomal dominant polycystic kidney disease. Exons 34-41 and 43-46 were assayed using PCR amplification and SSCP analysis followed by direct sequencing of amplicons presenting variant SSCP patterns. We have identified seven disease-causing mutations of which five are novel [c.10634-10656del; c.11587delG; IVS37-10C>A; c.11669-11674del; c.13069-13070ins39] and two have been reported previously [Q4010X; Q4041X]. Defects in this part of the gene thus account for 17% of our group of patients. Five of the seven sequence alterations detected are protein-truncating which is in agreement with mutation screening data for this part of the gene by other groups. The two other mutations are in-frame deletions or insertions which could destroy important functional properties of polycystin 1. These findings suggest that the first step toward cyst formation in PKD1 patients is the loss of one functional copy of polycystin 1, which indirectly supports the "two-hit" model of cystogenesis where a second somatic mutation inactivating the normal allele is necessary to occur for development of the disease condition.

• Kim UK et al.
• Novel mutations of the PKD1 gene in Korean patients with autosomal dominant polycystic kidney disease.
• Mutat Res. 2000; 432: 39-45
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• The gene for the most common form of autosomal dominant polycystic kidney disease (ADPKD), PKD1, has recently been characterized and shown to encode an integral membrane protein, polycystin-1, which is involved in cell-cell and cell-matrix interactions. Until now, approximately 30 mutations of the 3' single copy region of the PKD1 gene have been reported in European and American populations. However, there is no report of mutations in Asian populations. Using the polymerase chain reaction and single-strand conformation polymorphism (SSCP) analysis, 91 Korean patients with ADPKD were screened for mutation in the 3' single copy region of the PKD1 gene. As a result, we have identified and characterized six mutations: three frameshift mutations (11548del8bp, 11674insG and 12722delT), a nonsense mutation (Q4010X), and two missense mutations (R3752W and D3814N). Five mutations except for Q4010X are reported here for the first time. Our findings also indicate that many different mutations are likely to be responsible for ADPKD in the Korean population. The detection of additional disease-causing PKD1 mutations will help in identifying the location of the important functional regions of polycystin-1 and help us to better understand the pathophysiology of ADPKD.

• Koptides M, Deltas CC
• Autosomal dominant polycystic kidney disease: molecular genetics and molecular pathogenesis.
• Hum Genet. 2000; 107: 115-26
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• Mutations in three different genes, PKD1, PKD2 and PKD3, can cause a very similar clinical picture of the autosomal dominant form of polycystic kidney disease (ADPKD). Apparently, mutations in the PKD3 gene, which is still unmapped, are very rare, whereas PKD1 defects account for about 85% of cases. Although ADPKD is a frequent monogenic disorder affecting approximately 1:1000 individuals in the Caucasian population, progress in understanding its pathology was somewhat slow until relatively recently when the PKD1 and PKD2 genes were mapped and cloned. They are both large, being approximately 52 kb and 68 kb in length respectively, and in addition, PKD1 is fairly complex, thus complicating mutation detection. The gene products, polycystin-1 and polycystin-2, are trans-membranous glycoproteins and are considered to be involved in signalling pathways, in cooperation with additional partners. Immunostaining studies in both humans and mice have revealed information regarding the localization of polycystins and their role in the development and maintenance of nephrons. Recent experimentation from various laboratories has shown that loss of heterozygosity and acquired somatic second hits may account, at least partly, for the inter- and intrafamilial phenotypic heterogeneity of the disease, while at the same time, the existence of other modifying loci is also hypothesized. The two-hit hypothesis is admittedly a very attractive one in that it can explain many of the features of the disease, whereas recent data regarding a trains-heterozygous model for cystogenesis adds to the complexity of the molecular mechanisms that can lead to pathogenesis.

• Persu A, Devuyst O
• Transepithelial chloride secretion and cystogenesis in autosomal dominant polycystic kidney disease.
• Nephrol Dial Transplant. 2000; 15: 747-50

• Koptides M, Mean R, Demetriou K, Pierides A, Deltas CC
• Genetic evidence for a trans-heterozygous model for cystogenesis in autosomal dominant polycystic kidney disease.
• Hum Mol Genet. 2000; 9: 447-52
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• Polycystic kidney disease (ADPKD) is a condition with an autosomal dominant mode of inheritance and adult onset. Two forms of the disease, ADPKD1 and ADPKD2, caused by mutations in PKD1 and PKD2, respectively, are very similar, except that ADPKD1 patients run a more severe course. At the cellular level, ADPKD1 was first shown to be recessive, since somatic second hits are perhaps necessary for cyst formation. The near identical phenotype had suggested that ADPKD1 and ADPKD2 might have a similar pathogenesis and that the two gene products, poly- cystins 1 and 2, are part of a common developmental pathway. Work in transgenic mice showed that somatic loss of Pkd2 expression is necessary for renal cyst formation, and recently we showed that somatic mutations inactivating the inherited healthy allele were present in 9 of 23 cysts from a human ADPKD2 kidney, supporting a two-hit loss-of-function model for ADPKD2 cystogenesis. Here, we provide the first direct genetic evidence that polycystins 1 and 2 do interact, perhaps as part of a larger complex. In cystic DNA from a kidney of an ADPKD1 patient, we showed somatic mutations not only in the PKD1 gene of certain cysts, but also in the PKD2 gene of others, generating a trans -heterozygous state with mutations in both genes. One mutation in PKD1 is of germinal nature and the mutation in the PKD2 gene is of somatic nature. The implications of such a situation are enormous, not only for ADPKD, but also for many other conditions with phenotypic heterogeneity and age-dependent penetrance.

• Koptides M et al.
• Screening of the PKD1 duplicated region reveals multiple single nucleotide polymorphisms and a de novo mutation in Hellenic polycystic kidney disease families.
• Hum Mutat. 2000; 16: 176-176
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• Mutations in the PKD1 gene account for approximately 85% of cases with autosomal dominant polycystic kidney disease (ADPKD1; MIM# 601313), which is considered one of the most frequent monogenic disorders, with a frequency of approximately 1:1000. The main symptom is the formation of fluid-filled cysts in the kidneys and less often in other organs, such as the liver and pancreas. Since the cloning of the gene many mutations have been identified, although the screening is hampered by several unique features of this gene, the most significant one being that approximately 70% of the sequence at the 5'-end, is reiterated elsewhere on chromosome 16 with homology approaching 95%. Here, we used an oligonucleotide primer anchored in the unique part in exon 34, paired with a forward primer in exon 23 for specifically amplifying PKD1 sequences. We screened for mutations in samples from 32 Hellenic ADPKD families. We detected seven sequence variants, five of which most probably are single nucleotide polymorphisms (SNPs), especially useful for linkage analysis and disease association studies. One is a missense change, segregating with ADPKD in one family. The last one is a missense non-conservative change, H2921P, which appeared de novo in the proband, concurrently with the disease phenotype, and was passed on to another two generations. Two siblings who inherited the same haplotype as the proband, but not the de novo mutation, were not affected. This is only the fourth case of a molecularly documented de novo mutation in ADPKD. Somatic mosaicism in peripheral blood leukocytes of the proband was tested and excluded. Hum Mutat 16:176, 2000.

• Mallat SG, el Imad Z, Kabalan S, Khabbouth J
• Genetics in adult polycystic kidney disease: how far can we go?
• J Med Liban. 1999; 47: 286-7

• Thomas R, McConnell R, Whittacker J, Kirkpatrick P, Bradley J, Sandford R
• Identification of mutations in the repeated part of the autosomal dominant polycystic kidney disease type 1 gene, PKD1, by long-range PCR.
• Am J Hum Genet. 1999; 65: 39-49
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• We have used long-range PCR to identify mutations in the duplicated part of the PKD1 gene. By means of a PKD1-specific primer in intron 1, an approximately 13.6-kb PCR product that includes exons 2-15 of the PKD1 gene has been used to search for mutations, by direct sequence analysis. This region contains the majority of the predicted extracellular domains of the PKD1-gene product, polycystin, including the 16 novel PKD domains that have similarity to immunoglobulin-like domains found in many cell-adhesion molecules and cell-surface receptors. Direct sequence analysis of exons encoding all the 16 PKD domains was performed on PCR products from a group of 24 unrelated patients with autosomal dominant polycystic kidney disease (ADPKD [MIM 173900]). Seven novel mutations were found in a screening of 42% of the PKD1-coding region in each patient, representing a 29% detection rate; these mutations included two deletions (one of 3 kb and the other of 28 bp), one single-base insertion, and four nucleotide substitutions (one splice site, one nonsense, and two missense). Five of these mutations would be predicted to cause a prematurely truncated protein. Two coding and 18 silent polymorphisms were also found. When, for the PKD1 gene, this method is coupled with existing mutation-detection methods, virtually the whole of this large, complex gene can now be screened for mutations.

• Iglesias DM et al.
• [Autosomal dominant polycystic kidney disease: detection of a new mutation in the PKD1 gene]
• Medicina (B Aires). 1999; 59: 133-7
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• Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by genetic heterogeneity. Up to three loci are involved in this disease, PKD1 on chromosome 16p13.3, PKD2 on 4q21, and a third locus of unknown location. Since the identification of the PKD1 gene, the interest was centered in the characterization of the mutations responsible for the disease. Most mutations found were diverse and situated throughout the gene with no phenotypic correlation. Here we describe a new mutation in exon 44 from PKD1 gene in a family previously characterized as PKD1 by linkage analysis. The mutation is a single base substitution from a C to a T at position 12220 originating a stop codon at the mutation site. This would lead to premature termination and the formation of a truncated protein lacking part of the carboxi-terminus.

• Veldhuisen B, Spruit L, Dauwerse HG, Breuning MH, Peters DJ
• Genes homologous to the autosomal dominant polycystic kidney disease genes (PKD1 and PKD2).
• Eur J Hum Genet. 1999; 7: 860-72
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• Autosomal Dominant Polycystic Kidney Disease (ADPKD), a common inherited disease leading to progressive renal failure, can be caused by a mutation in either the PKD1 or PKD2 gene. Both genes encode for putative transmembrane proteins, polycystin-1 and polycystin-2, which show significant homology to each other and are believed to interact at their carboxy termini. To identify genes that code for related proteins we searched for homologous sequences in several databases and identified one partial cDNA and two genomic sequences with significant homology to both polycystin-1 and - 2. Further analysis revealed one novel gene, PKD2L2, located on chromosome band 5q31, and two recently described genes, PKD2L and PKDREJ, located on chromosome bands 10q31 and 22q13.3, respectively. PKD2L2 and PKD2L, which encode proteins of 613 and 805 amino acids, are approximately 65% similar to polycystin-2. The third gene, PKDREJ, encodes a putative 2253 amino acid protein and shows about 35% similarity to both polycystin-1 and polycystin-2. For all the genes expression was found in testis. Additional expression of PKD2L was observed in retina, brain, liver and spleen by RT-PCR. Analyses of five ADPKD families without clear linkage to either the PKD1 or PKD2 locus showed no linkage to any of the novel loci, excluding these genes as the cause of ADPKD in these families. Although these genes may not be involved in renal cystic diseases, their striking homology to PKD2 and PKD1 implies similar roles and may contribute to elucidating the function of both polycystin-1 and polycystin-2.

• Sandford R, Mulroy S, Foggensteiner L
• The polycystins: a novel class of membrane-associated proteins involved in renal cystic disease.
• Cell Mol Life Sci. 1999; 56: 567-79
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• Polycystin-1, polycystin-2 and polycystin-L are the predicted protein products of the PKD1, PKD2 and PKDL genes, respectively. Mutations in PKD1 and PKD2 are responsible for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). This condition is one of the commonest mendelian disorders of man with a prevalence of 1:800 and is responsible for nearly 10% of cases of end-stage renal failure in adults. The cloning of PKD1 and PKD2 in recent years has provided the initial steps in defining the mechanisms underlying renal cyst formation in this condition, with the aim of defining pharmacological and genetic interventions that may ameliorate the diverse and often serious clinical manifestations of this disease. The PKD genes share regions of sequence similarity, and all predictintegral membrane proteins. Whilst the predicted protein domain structure of polycystin-1 suggests it is involved in cell-cell or cell-matrix interactions, the similarity of polycystin-2 and polycystin-L to the pore-forming domains of some cation channels suggests that they all form subunits of a large plasma membrane ion channel. In the few years since the cloning of the PKD genes, a consensus that defines the range of mutations, expression pattern, interactions and functional domains of these genes and their protein products is emerging. This review will therefore attempt to summarise these data and provide an insight in to the key areas in which polycystin research is unravelling the mechanisms involved in renal cyst formation.

• van Adelsberg J
• Peptides from the PKD repeats of polycystin, the PKD1 gene product, modulate pattern formation in the developing kidney.
• Dev Genet. 1999; 24: 299-308
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• Mutations in the PKD1 gene cause the majority of cases of autosomal dominant polycystic kidney disease. The PKD1 gene codes for a protein of unknown function, polycystin-1, that is predicted to be a receptor. Its large extracellular domain contains 16 copies of novel motif, the PKD repeat, that is likely to be a ligand binding domain based on its similarity to immunoglobulin domains. These observations suggested that soluble fragments of the extracellular domain of polycystin-1 could be used as competitive inhibitors of polycystin function in a suitable model system. Polycystin-1 is highly expressed in the ureteric bud and other branching epithelia during development and interacts with beta-catenin, a molecule known to play a role in branching morphogenesis. These data suggested that polycystin-1 might play a role in branching morphogenesis. I show here that peptides derived from the PKD repeats of polycystin-1 caused an asymmetric pattern of ureteric bud branching in cultured kidney rudiments. Treatment of kidney rudiments with experimental but not control peptides reduced both the number of ureteric bud branches and the number of nephrons. Experimental peptides produced significant morphogenetic effects at concentrations < or = 0.1 mM. These data suggest that polycystin-1 plays a role in branching morphogenesis by the ureteric bud.

• Yu S, Mei C, Hu Y
• [Cloning of mouse polycystic kidney disease 1 gene]
• Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 1999; 16: 364-7
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• OBJECTIVE: To obtain mouse Polycystic kidney disease 1(PKD1) gene by plagues in situ hybridization from a genomic library. METHODS: With the use of partial mouse PKD1 genomic DNA fragments amplified by PCR as probes, a genomic library of 129SvTer mouse in bacteriophage vector was screened by plagues in situ hybridization. The inserts of genomic DNA fragments were analyzed by Southern blot, subclone and verified by sequencing. RESULTS: A positive phage clone was obtained after four-round screening. The sequence of the genomic DNA fragments inserted in the positive clone was in accordance with that of the Genebank. CONCLUSION: The authors found that the length and structure of mouse PKD1 genomic DNA fragments obtained from a genomic library were available to construct a replacement targeting vector.

• Hughes J, Ward CJ, Aspinwall R, Butler R, Harris PC
• Identification of a human homologue of the sea urchin receptor for egg jelly: a polycystic kidney disease-like protein.
• Hum Mol Genet. 1999; 8: 543-9
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• Previous studies have shown sequence similarity between a region of the autosomal dominant polycystic kidney disease (ADPKD) protein, polycystin-1 and a sea urchin sperm glycoprotein involved in fertilization, the receptor for egg jelly (suREJ). We have analysed sequence databases for novel genes encoding PKD/REJ-like proteins and found a significant region of homology to a large open reading frame in genomic sequence from human chromosome 22. Northern analysis showed that this is a functional gene [termed the polycystic kidney disease and receptor for egg jelly related gene ( PKDREJ )], but unlike polycystin-1, has a very restricted expression pattern; the approximately 8 kb transcript was found exclusively in testis, coincident with the timing of sperm maturation. The PKDREJ transcript was cloned by screening a testis cDNA library and RT-PCR which revealed a 7660 bp mRNA terminating with a 900 bp 3'UTR and a polyA tail. Comparison with genomic sequence showed that PKDREJ is intronless; sequencing the mouse orthologue revealed a similar structure. The predicted human PKDREJ protein has 2253 amino acids (calculated molecular mass 255 kDa) and sequence similarity over approximately 2000 amino acids with polycystin-1, corresponding to the predicted membrane associated region and the area of homology ( approximately 1000 amino acids) with the suREJ protein (the REJ module). The suREJ protein binds the glycoprotein coat of the egg (egg jelly), triggering the acrosome reaction, which transforms the sperm into a fusogenic cell. The sequence similarity and expression pattern suggests that PKDREJ is a mammalian equivalent of the suREJ protein and therefore may have a central role in human fertilization.

• Qian F, Watnick TJ
• Somatic mutation as mechanism for cyst formation in autosomal dominant polycystic kidney disease.
• Mol Genet Metab. 1999; 68: 237-42

• Harris PC
• Autosomal dominant polycystic kidney disease: clues to pathogenesis.
• Hum Mol Genet. 1999; 8: 1861-6
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• Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutation of one of two genes: PKD1 (16p13.3) or PKD2 (4q13-23). PKD1 accounts for approximately 85% of pedigrees and is associated with significantly more severe cystic disease. The ADPKD genes encode proteins, polycystin-1 and polycystin-2, which are very different in size and structure, but which have a region of homology and may interact as part of the same complex. Polycystin-1 is a large, integral membrane protein ( approximately 460 kDa) predicted to be involved in cell-cell and/or cell-matrix interactions. Polycystin-2 ( approximately 110 kDa) is related to polycystin-1 and voltage-activated and transient receptor potential channel subunits, suggesting that the polycystins may also be associated with ion transport. A polycystin complex could regulate cellular events (that are abnormal in ADPKD) in response to specific extracellular cues, mediated by controlling cellular Ca(2+)levels and/or other signalling pathways. Recently, two further polycystin-like molecules have been identified, indicating roles for this novel protein family beyond the kidney. A wide range of different mutations to the PKD1 or PKD2 gene have been detected, most predicted to truncate and inactivate the proteins. A somatic second hit may be required for focal cyst development, although there is widespread immunohistochemical evidence of polycystin expression in cystic epithelia. Disruption of the mouse Pkd1 gene leads to death in the perinatal period with massive cystic expansion in homozygotes and age-related cyst development in heterozygotes. Normal renal development in Pkd1(del34/del34)mice up to embryonic day approximately 15.5 suggests a role for polycystin-1 in developing and maintaining the tubular architecture, consistent with the localization of the protein, rather than nephron induction. Renal cystic disease in homo- and heterozygotes of a Pkd2 mouse model with a disrupted exon 1 inserted in tandem with the normal exon (and prone to somatic recombination, which inactivates the gene) supports a role for somatic events in cystogenesis.

• Afzal AR, Hand M, Ternes-Pereira E, Saggar-Malik A, Taylor R, Jeffery S
• Novel mutations in the 3 region of the polycystic kidney disease 1 (PKD1) gene.
• Hum Genet. 1999; 105: 648-53
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• Mutation screening in 90 unrelated ADPKD1 patients was carried out on some of the exons in the single copy area (37, 38, 39, 44, 45) using genomic PCR and SSCP. Four novel mutations were found: a 15 bp in-frame deletion in exon 39 [nt11449 (del 15)], a 2 bp deletion in exon 44 [nt12252 (del 2)], a G insertion in exon 44 [nt12290 (Ins G)], and a GTT in-frame deletion in exon 45 [nt12601 (del 3)].

• Watnick T, Germino GG
• Molecular basis of autosomal dominant polycystic kidney disease.
• Semin Nephrol. 1999; 19: 327-43
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• Recent studies have identified the genes mutated in the two major forms of autosomal dominant polycystic kidney disease, PKD1 and PKD2. The PKD1 gene product is likely to be a very large membrane-associated glycoprotein that functions as a receptor for cell-cell or cell-matrix interactions. PKD2 has significant homology to the family of voltage-activated calcium channels. Both proteins are expressed in the developing kidney and appear to have an overlapping pattern of expression. Several studies suggest that the gene products are interacting partners of a signaling pathway. Studies of human tissue suggest a two-hit genetic mechanism is responsible for both forms of the disease. Consistent with this hypothesis, murine models engineered with loss-of-function mutations of Pkd1 or Pkd2 develop cystic disease in the homozygous state. In these animals, renal development proceeds normally through day 15, at approximately which time renal cysts begin to form. The studies suggest an essential role for the PKD proteins in regulating later stages of tubular maturation. The animal models will be useful resources for defining the pathogenesis of autosomal dominant polycystic kidney disease and testing various therapeutic interventions. The two-hit model has potentially important clinical implications.

• Branger B
• Unilateral form of polycystic kidney disease.
• Nephrol Dial Transplant. 1999; 14: 2775-6

• Bycroft M et al.
• The structure of a PKD domain from polycystin-1: implications for polycystic kidney disease.
• EMBO J. 1999; 18: 297-305
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• Most cases of autosomal dominant polycystic kidney disease (ADPKD) are the result of mutations in the PKD1 gene. The PKD1 gene codes for a large cell-surface glycoprotein, polycystin-1, of unknown function, which, based on its predicted domain structure, may be involved in protein-protein and protein-carbohydrate interactions. Approximately 30% of polycystin-1 consists of 16 copies of a novel protein module called the PKD domain. Here we show that this domain has a beta-sandwich fold. Although this fold is common to a number of cell-surface modules, the PKD domain represents a distinct protein family. The tenth PKD domain of human and Fugu polycystin-1 show extensive conservation of surface residues suggesting that this region could be a ligand-binding site. This structure will allow the likely effects of missense mutations in a large part of the PKD1 gene to be determined.

• Piontek KB, Germino GG
• Murine Pkd1 introns 21 and 22 lack the extreme polypyrimidine bias present in human PKD1.
• Mamm Genome. 1999; 10: 194-6

• de Almeida E, Martins Prata M, de Almeida S, Lavinha J
• Long-term follow-up of a family with autosomal dominant polycystic kidney disease type 3.
• Nephrol Dial Transplant. 1999; 14: 631-4
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• BACKGROUND: Autosomal dominant polycystic kidney disease is one of the most common hereditary diseases in man with an estimated prevalence of 1:1000. At least three genetic loci are responsible for the development of the disease. PKD1 localized to 16p13 is the most common gene, contributing to almost 85% of all cases, is associated with the most severe form. PKD2, localized to 4q21-23, responsible for almost all the remaining cases, is associated with a milder form. Up to now, only five families have been reported unlinked to the two most common genetic defects, and therefore little is known about the clinical findings of the non-PKD1/PKD2 families. METHODS: In this report we describe the clinical findings of 18 patients of a non-PKD1/PKD2 family, with a mean follow-up of 52 months (range 3-133 months) in our outpatient clinic. RESULTS: Of the 10 patients older than 40 years, nine were hypertensive; in this age group eight patients exhibited renal failure (two of them were on dialysis) and six had hepatic cysts. In eight patients younger than 40 years, the only clinical finding was hypertension in two. Considerable variation in the rate of progression to renal failure among members of this family was found; on the other hand, some patients did not exhibit any signs of progression. CONCLUSION: This family exhibits a more aggressive phenotype, in contrast with the majority of the described non-PKD1/non-PKD2 families.

• Thongnoppakhun W, Wilairat P, Vareesangthip K, Yenchitsomanus PT
• Long RT-PCR Amplification of the entire coding sequence of the polycystic kidney disease 1 (PKD1) gene.
• Biotechniques. 1999; 26: 126-32
• Display abstract

• Characterization of mutations of the PKD1 gene has been limited by the fact that three-fourths of this gene at its 5' end is homologous to sequences of at least three other genes on the same chromosome. We have therefore developed a method of long reverse transcription PCR for selective amplification of the entire coding sequence of the PKD1 gene from its mRNA. A PCR primer specific to the sequence in the 3' unique region of the PKD1 gene was synthesized for use coupled with a primer binding to sequence in the homologous region at a distance of about 13.6 kb apart. The commercial availability of RNase H-free reverse transcriptase for long cDNA synthesis and of an enzyme mixture containing Taq and Pfu DNA polymerases for long-range PCR have made this development possible. The long PCR product was proven to be derived from PKD1-mRNA. The results clearly indicated that the long PCR product contained the coding sequence derived from PKD1-mRNA. To our knowledge, this is the first report of a procedure that can reproducibly isolate full-length PKD1 coding sequence from its mRNA transcript, which will prove useful for screening and characterization of mutations in the PKD1 gene.

• Jeffery S, Saggar-Malik AK, Economides DL, Blackmore SE, MacDermot KD
• Apparent normalisation of fetal renal size in autosomal dominant polycystic kidney disease (PKD1).
• Clin Genet. 1998; 53: 303-7
• Display abstract

• We present a family with adult onset autosomal dominant polycystic kidney disease (ADPKD) in two generations, linked to the PKD1 locus and with paternal transmission to the fetus. The fetus carried the PKD1 haplotype and was, therefore a gene carrier. Progressive hyperechogenic renal enlargement, but no cysts, was documented by serial fetal ultrasounds at 21, 23 and 34 weeks of gestation. Surprisingly, the newborn renal scan showed normal sized kidneys with apparently normal corticomedullary differentiation. However, at 11 months of age, the evolution of cysts in one kidney, and then in the other kidney at 20 months, was documented by ultrasound in the absence of clinical symptoms or signs. The observed normalisation of fetal renal ultrasound appearances at birth has not previously been described in fetuses presenting with PKD1.

• Liu PC, Chen YW, Shibuya H, Lubahn DB, Johnson GS
• A length polymorphism in an intron of the canine polycystic kidney disease 1 gene.
• Anim Genet. 1998; 29: 322-3

• Watnick TJ et al.
• Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease.
• Mol Cell. 1998; 2: 247-51
• Display abstract

• Autosomal dominant polycystic kidney disease (ADPKD), Type I is a common genetic disorder and an important cause of renal failure. The disease is characterized by progressive cyst formation in a variety of organs including the kidney, liver and pancreas. We have previously shown that in the case of PKD1, renal cyst development is likely to require somatic inactivation of the normal allele coupled to a germline PKD1 mutation. In this report, we have used unique reagents to show that intragenic, somatic mutations are common in hepatic cysts. All pathogenic mutations were shown to have altered the previously normal copy of the gene. These data extend the "two-hit" model of cystogenesis to include a second focal manifestation of the disease.

• Nomura H et al.
• Identification of PKDL, a novel polycystic kidney disease 2-like gene whose murine homologue is deleted in mice with kidney and retinal defects.
• J Biol Chem. 1998; 273: 25967-73
• Display abstract

• Polycystin-1 and polycystin-2 are the products of PKD1 and PKD2, genes that are mutated in most cases of autosomal dominant polycystic kidney disease. Polycystin-2 shares approximately 46% homology with pore-forming domains of a number of cation channels. It has been suggested that polycystin-2 may function as a subunit of an ion channel whose activity is regulated by polycystin-1. Here we report the identification of a human gene, PKDL, which encodes a new member of the polycystin protein family designated polycystin-L. Polycystin-L has 50% amino acid sequence identity and 71% homology to polycystin-2 and has striking sequence and structural resemblance to the pore-forming alpha1 subunits of Ca2+ channels, suggesting that polycystin-L may function as a subunit of an ion channel. The full-length transcript of PKDL is expressed at high levels in fetal tissues, including kidney and liver, and down-regulated in adult tissues. PKDL was assigned to 10q24 by fluorescence in situ hybridization and is linked to D10S603 by radiation hybrid mapping. There is no evidence of linkage to PKDL in six ADPKD families that are unlinked to PKD1 or PKD2. The mouse homologue of PKDL is deleted in Krd mice, a deletion mutant with defects in the kidney and eye. We propose that PKDL is an excellent candidate for as yet unmapped cystic diseases in man and animals.

• Daniells C, Maheshwar M, Lazarou L, Davies F, Coles G, Ravine D
• Human gene mutations. Gene symbol: PKD1. Disease: Polycystic kidney disease.
• Hum Genet. 1998; 102: 127-127

• Pennekamp P et al.
• Characterization of the murine polycystic kidney disease (Pkd2) gene.
• Mamm Genome. 1998; 9: 749-52
• Display abstract

• Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequent genetically transmitted disorders among Europeans with an attributed frequency of 0.1%. The two most common genetic determinants for ADPKD are the PKD1 and PKD2 genes. In this study we report the genomic structure and pattern of expression of the Pkd2 gene, the murine homolog of the human PKD2 gene. Pkd2 is localized on mouse Chromosome (Chr) 5 proximal to anchor marker D5Mit175, spans at least 35 kb of the mouse genome, and consists of 15 exons. Its translation product consists of 966 amino acids, and the peptide shows a 95% homology to human polycystin2. Functional domains are particularly well conserved in the mouse homolog. The expression of mouse polycystin2 in the developing embryo at day 12.5 post conception is localized in mesenchymally derived structures. In the adult mouse, the protein is mostly expressed in kidney, which suggests its functional relevance for this organ.

• Pei Y et al.
• A novel frameshift mutation induced by an adenosine insertion in the polycystic kidney disease 2 (PKD2) gene.
• Kidney Int. 1998; 53: 1127-32
• Display abstract

• Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common Mendelian disorders and is genetically heterogeneous. Linkage studies have shown that the majority (approximately 85%) of ADPKD cases are due to mutations in PKD1 on chromosome 16p13.3, while mutations in PKD2 on chromosome 4q21-q23 are thought to account for most of the remaining cases. In this report, we describe the mutation in a large four-generation ADPKD family (TOR-PKD77) which we had mapped to the PKD2 locus by linkage analysis. In this family, we screened for mutations by directly sequencing two nested RT-PCR fragments (PKD2N1 and PKD2N2) that cover approximately 90% of the PKD2 open reading frame. In the affected members, we identified a novel single adenosine insertion (2160InsA) in the PKD2N2 fragment. This mutation occurred in the polyadenosine tract (nt2152-2159) of exon 11 and is predicted to result in a frameshift with premature translation termination of the PKD2 product, polycystin 22, immediately after codon 723. The truncated polycystin 2 is predicted to lack the calcium-binding EF-hand domain and two cytoplasmic domains required for the homodimerization of polycystin 2 with itself and for the heterodimerization of polycystin 2 with polycystin 1.

• Carone FA, Bacallao R, Kanwar Y
• Role of the matrix in autosomal dominant polycystic kidney disease.
• Ren Fail. 1998; 20: 181-9
• Display abstract

• At present, even though we have accumulated a wealth of knowledge regarding structural, and molecular changes in ADPKD, the primary cause of the disease remains unknown. Obviously the gap in our understanding of the nature of the disease has been narrowed substantially over the past decade. With current techniques and efforts, the ultimate mystery of ADPKD should be resolved during the next decade.

• Torra R et al.
• [Clinical, genetic and molecular studies on autosomal dominant polycystic kidney disease]
• Med Clin (Barc). 1998; 110: 481-7
• Display abstract

• BACKGROUND: Two genes causing autosomal dominant polycystic kidney disease (ADPKD), PKD1 and PKD2, have been described. In the present work we study, by means of linkage analysis, the genetic heterogeneity in our population as well as the clinical differences between PKD1 and PKD2. SUBJECTS AND METHODS: 316 subjects belonging to 49 unrelated ADPKD families have been studied by means of 3 microsatellites for PKD1 and 3 for PKD2 to differentiate if they have ADPKD type 1 or 2. The techniques used to analyze the microsatellites have been the chemiluminescence and the silver satining techniques. All the subjects underwent a complete physical examination and a sonographic scan. Clinical and molecular results have been correlated. RESULTS: Genetic heterogeneity has been proved, with 85% of families linked to PKD1 and 15% to PKD2. The disease is more severe in PKD1, with an earlier age at diagnosis (27.4 vs. 41.4 years; p = 0.0002), a younger age at the onset of end stage renal disease (53.4 vs. 72.7 years, p < 0.00001), and earlier age at diagnosis of hypertension (34.8 vs. 49.7 years; p = 0.001) and a higher prevalence of hypertension for all groups of age. In both forms of ADPKD there were families showing anticipation (8/44 for PKD1 and 2/5 for PKD2) but this was not a widespread phenomenon. Our data do not support the phenomenon of genetic imprinting for this disease. CONCLUSION: In the population of Catalonia, Spain, PKD1 accounts for 85% of families with autosomal dominant polycystic kidney disease and PKD2 accounts for the remaining 15%. PKD1 form is more severe than PKD2.

• Watnick TJ, Gandolph MA, Weber H, Neumann HP, Germino GG
• Gene conversion is a likely cause of mutation in PKD1.
• Hum Mol Genet. 1998; 7: 1239-43
• Display abstract

• Approximately 70% of the gene responsible for the most common form of autosomal dominant polycystic kidney disease ( PKD1 ) is replicated in several highly homologous copies located more proximally on chromosome 16. We recently have described a novel technique for mutation detection in the duplicated region of PKD1 that circumvents the difficulties posed by these homologs. We have used this method to identify two patients with a nearly identical cluster of base pair substitutions in exon 23. Since pseudogenes are known to be reservoirs for mutation via gene conversion events for a number of other diseases, we decided to test whether these sequence differences in PKD1 could have arisen as a result of this mechanism. Using changes in restriction digest patterns, we were able to show that these sequence substitutions are also present in N23HA, a rodent-human somatic cell hybrid that contains only the PKD1 homologs. Moreover, these changes were also detected in total DNA from several affected and unaffected individuals that did not harbor this mutation in their PKD1 gene copy. This is the first example of gene conversion in PKD1 , and our findings highlight the importance of using gene-specific reagents in defining PKD1 mutations.

• Harris PC, Watson ML
• Autosomal dominant polycystic kidney disease: neoplasia in disguise?
• Nephrol Dial Transplant. 1997; 12: 1089-90

• Torra R, Badenas C, Darnell A, Bru C, Escorsell A, Estivill X
• Autosomal dominant polycystic kidney disease with anticipation and Caroli's disease associated with a PKD1 mutation. Rapid communication.
• Kidney Int. 1997; 52: 33-8
• Display abstract

• Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal hereditary disorder. Clinical expression of ADPKD shows interfamilial and intrafamilial variability. We screened for mutations the 3' region of the PKD1 gene, from exon 43 to exon 46, in a family showing anticipation and Caroli's disease and have found a 28 base pairs deletion in exon 46 (12801del28) and a new DNA variant in exon 43 (12184 C to G conserving Ala 3991) segregating with the disease. The mutation should result in a protein 44 amino acids longer then the wild-type PKD1. This PKD1 mutation manifests as typical adult-onset disease in the father, but in the proband, a 26-year-old man, ADPKD was diagnosed as a newborn and was associated with Caroli's disease at the age of 18 years. A renal biopsy performed in childhood disclosed a predominance of glomerular cysts. Mutation 12801del28 is the first molecular defect associated with Caroli's disease and the PKD1 phenotype. The finding of the same mutation in two different members of the same family with different expression of the disease indicates that the phenotypic variation in ADPKD must be due to modifying factors that may radically affect the course of the disease.

• Merta M et al.
• DNA diagnosis and clinical manifestations of autosomal dominant polycystic kidney disease.
• Folia Biol (Praha). 1997; 43: 201-4
• Display abstract

• At least 2 genes, detectable by DNA methods, encode autosomal dominant polycystic kidney disease (ADPKD), which remains the most frequent and serious hereditary renal disease. PKD1 gene, localized on chromosome 16, responds for the clinical course in the majority of ADPKD patients, whereas PKD2 gene, localized on chromosome 4, is responsible for less than 10-15% of cases, with presumed milder phenotypic manifestations. To start the clinical and genetic correlation in patients with different genotypes (PKD1 vs. PKD2) in the Czech population, a pilot group of 88 patients with ADPKD was analysed. Families with PKD1 (n = 44) represented 95.6% and families with PKD2 (n = 2) 4.4% of all families investigated (n = 46). Our clinical analysis, yet based only on a limited number of PKD2 subjects, does not definitely support the concept of a milder phenotype and prognosis in PKD2 versus PKD1 patients, in terms of mean age of diagnosis (29 vs. 29 years), mean age at onset of arterial hypertension (33 vs. 33 years), more favourable renal function or ultrasound findings.

• Badenas C, Torra R, Darnell A, Estivill X
• Mutations and intragenic polymorphisms in the diagnosis of autosomal dominant polycystic kidney disease type 1.
• Contrib Nephrol. 1997; 122: 45-8

• Watnick TJ et al.
• An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection.
• Hum Mol Genet. 1997; 6: 1473-81
• Display abstract

• The gene for the most common and severe form of autosomal dominant polycystic kidney disease, PKD1, encodes a 14 kb mRNA that is predicted to result in an integral membrane protein of 4302 amino acids. The major challenge faced by researchers attempting to complete mutation analysis of the PKD1 gene has been the presence of several homologous loci also located on chromosome 16. Because the sequence of PKD1 and its homologs is nearly identical in the 5' region of the gene, most traditional approaches to mutation analysis cannot distinguish sequence variants occurring uniquely in PKD1. Therefore, only a small number of mutations have been identified to date and these have all been found in the 3', unique portion of the gene. In order to begin analysis of the duplicated region of PKD1, we have devised a novel strategy that depends on long-range PCR and a single gene-specific primer from the unique region of the gene to amplify a PKD1-specific template that spans exons 23-34. This 10 kb template, amplified from genomic DNA, can be employed for mutation analysis using a wide variety of sequence-based approaches. We have used our long-range PCR strategy to begin screening for sequence variants with heteroduplex analysis, and several affected individuals were discovered to have clusters of base pair substitutions in exons 23 and 25. In two patients, these changes, identified in exon 23, would be predicted to result in multiple amino acid substitutions in a short stretch of the protein. This clustering of base pair substitutions is unusual and suggests that mutation may result from unique structural features of the PKD1 gene.

• Veldhuisen B et al.
• A spectrum of mutations in the second gene for autosomal dominant polycystic kidney disease (PKD2).
• Am J Hum Genet. 1997; 61: 547-55
• Display abstract

• Recently the second gene for autosomal dominant polycystic kidney disease (ADPKD), located on chromosome 4q21-q22, has been cloned and characterized. The gene encodes an integral membrane protein, polycystin-2, that shows amino acid similarity to the PKD1 gene product and to the family of voltage-activated calcium (and sodium) channels. We have systematically screened the gene for mutations by single-strand conformation-polymorphism analysis in 35 families with the second type of ADPKD and have identified 20 mutations. So far, most mutations found seem to be unique and occur throughout the gene, without any evidence of clustering. In addition to small deletions, insertions, and substitutions leading to premature translation stops, one amino acid substitution and five possible splice-site mutations have been found. These findings suggest that the first step toward cyst formation in PKD2 patients is the loss of one functional copy of polycystin-2.

• Lohning C, Nowicka U, Frischauf AM
• The mouse homolog of PKD1: sequence analysis and alternative splicing.
• Mamm Genome. 1997; 8: 307-11
• Display abstract

• We have cloned and sequenced the mouse transcript homologous to human polycystic kidney disease 1 (PKD1). The predicted protein is 79% identical to human PKD1 and shows the presence of most of the domains identified in the human sequence. Since the mouse homolog is transcribed from a unique gene and there are no transcribed, closely related copies as has been observed for human PKD1, we have been able to investigate alternative splicing of the transcript. At the junction of exons 12 and 13, several different splicing variants lead to a predicted protein that would be secreted. These forms are predominantly found in newborn brain, while in kidney the transcript homologous to the previously described human RNA predominates.

• Turco AE, Rossetti S, Bresin E, Englisch S, Corra S, Pignatti PF
• Three novel mutations of the PKD1 gene in Italian families with autosomal dominant polycystic kidney disease.
• Hum Mutat. 1997; 10: 164-7

• Ong AC
• Renal disease. II. The polycystic kidney disease 1 (PKD-1) gene: an important clue in the study of renal cyst formation.
• J R Coll Physicians Lond. 1997; 31: 141-6

• Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG
• PKD1 interacts with PKD2 through a probable coiled-coil domain.
• Nat Genet. 1997; 16: 179-83
• Display abstract

• Autosomal dominant polycystic kidney disease (ADPKD) describes a group of at least three genetically distinct disorders with almost identical clinical features that collectively affects 1:1,000 of the population. Affected individuals typically develop large cystic kidneys and approximately one half develop end-stage renal disease by their seventh decade. It has been suggested that the diseases result from defects in interactive factors involved in a common pathway. The recent discovery of the genes for the two most common forms of ADPKD has provided an opportunity to test this hypothesis. We describe a previously unrecognized coiled-coil domain within the C terminus of the PKD1 gene product, polycystin, and demonstrate that it binds specifically to the C terminus of PKD2. Homotypic interactions involving the C terminus of each are also demonstrated. We show that naturally occurring pathogenic mutations of PKD1 and PKD2 disrupt their associations. We have characterized the structural basis of their heterotypic interactions by deletional and site-specific mutagenesis. Our data suggest that PKD1 and PKD2 associate physically in vivo and may be partners of a common signalling cascade involved in tubular morphogenesis.

• Peral B et al.
• Identification of mutations in the duplicated region of the polycystic kidney disease 1 gene (PKD1) by a novel approach.
• Am J Hum Genet. 1997; 60: 1399-410
• Display abstract

• Mutation screening of the major autosomal dominant polycystic kidney disease gene (PKD1) has been complicated by the large transcript size (> 14 kb) and by reiteration of the genomic area encoding 75% of the protein on the same chromosome (the HG loci). The sequence similarity between the PKD1 and HG regions has precluded specific analysis of the duplicated region of PKD1, and consequently all previously described mutations map to the unique 3' region of PKD1. We have now developed a novel anchored reverse-transcription-PCR (RT-PCR) approach to specifically amplify duplicated regions of PKD1, employing one primer situated within the single-copy region and one within the reiterated area. This strategy has been incorporated in a mutation screen of 100 patients for more than half of the PKD1 exons (exons 22-46; 37% of the coding region), including 11 (exons 22-32) within the duplicated gene region, by use of the protein-truncation test (PTT). Sixty of these patients also were screened for missense changes, by use of the nonisotopic RNase cleavage assay (NIRCA), in exons 23-36. Eleven mutations have been identified, six within the duplicated region, and these consist of three stop mutations, three frameshifting deletions of a single nucleotide, two splicing defects, and three possible missense changes. Each mutation was detected in just one family (although one has been described elsewhere); no mutation hot spot was identified. The nature and distribution of mutations, plus the lack of a clear phenotype/genotype correlation, suggest that they may inactivate the molecule. RT-PCR/PTT proved to be a rapid and efficient method to detect PKD1 mutations (differentiating pathogenic changes from polymorphisms), and we recommend this procedure as a firstpass mutation screen in this disorder.

• Van Raay TJ, Foskett SM, Connors TD, Klinger KW, Landes GM, Burn TC
• The NTN2L gene encoding a novel human netrin maps to the autosomal dominant polycystic kidney disease region on chromosome 16p13.3.
• Genomics. 1997; 41: 279-82
• Display abstract

• The netrins define a family of chemotropic factors that have been shown to play a central role in axon guidance. We identified two exon traps encoding netrin-like sequences during the assembly of a transcriptional map for the genomic interval surrounding the polycystic kidney disease type 1 and tuberous sclerosis type 2 genes. We describe the characterization of a novel human netrin-2-like gene, designated NTN2L, and its transcript. The genomic interval containing the NTN2L gene was sequenced, and the coding region was predicted based on computer analysis. The structure of the NTN2L gene has been confirmed utilizing nested RT-PCR. The NTN2L gene is predicted to encode a 580-amino-acid protein having homology to the chicken and Drosophila netrins and to Caenorhabditis elegans UNC-6. The NTN2L gene has a restricted pattern of expression; its transcript is undetectable by Northern analysis in all tissues examined, but can be recovered from spinal cord RNA by RT-PCR. This report represents the first description and characterization of a human netrin.

• Wu G et al.
• Molecular cloning, cDNA sequence analysis, and chromosomal localization of mouse Pkd2.
• Genomics. 1997; 45: 220-3
• Display abstract

• The gene responsible for the second form of autosomal dominant polycystic kidney disease, PKD2, has recently been identified. We now describe the cloning, genomic localization, cDNA sequence, and expression analysis of its murine homologue, Pkd2. The cloned cDNA sequence is 5134 bp long and is predicted to encode a 966-amino-acid integral membrane protein with six membrane-spanning domains and intracellular NH2 and COOH termini. Pkd2 is highly conserved with 91% identity and 98% similarity to polycystin-2 at the amino acid level. Pkd2 mRNA is widely expressed in mouse tissues. Pkd2 maps to mouse Chromosome 5 and is excluded as a candidate gene for previously mapped mouse mutations resulting in a polycystic kidney phenotype.

• Roelfsema JH et al.
• Mutation detection in the repeated part of the PKD1 gene.
• Am J Hum Genet. 1997; 61: 1044-52
• Display abstract

• The principle cause of one of the most prevalent genetic disorders, autosomal dominant polycystic kidney disease, involves mutations in the PKD1 gene. However, since its identification in 1994, only 27 mutations have been published. Detection of mutations has been complicated because the greater part of the gene lies within a genomic region that is reiterated several times at another locus on chromosome 16. Amplification of DNA fragments in the repeated part of the PKD1 gene will lead to coamplification of highly homologous fragments derived from this other locus. These additional fragments severely hamper point-mutation detection. None of the point mutations published to date are located in the repeated part of the PKD1 gene. However, we have reduced the problems posed by the strong homology, by using the protein-truncation test, and we have identified eight novel mutations, seven of which are located in the repeated part of the PKD1 gene.

• Toth T, Nagy B
• [Molecular genetic study of type I autosomal dominant polycystic kidney disease]
• Orv Hetil. 1997; 138: 2638-2638

• Bresin E, Rossetti S, Englisch S, Corra S, Pignatti PF, Turco AE
• A common polymorphism in exon 46 of the human autosomal dominant polycystic kidney disease 1 gene (PKD1).
• Mol Cell Probes. 1996; 10: 463-5
• Display abstract

• Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common single gene diseases in humans. We have identified a synonymous T to C transition polymorphism in exon 46 of the PKD1 gene (12838T-->C, Pro4209Pro). The polymorphism was present with similar frequencies in ADPKD patients and unaffected individuals. The heterozygosity, determined in 89 Italian individuals, was 0.347. The frequency of the rarer allele was 0.222. This polymorphism is easy to determine as it abolishes a naturally occurring Ddel restriction site. The availability of an additional intragenic marker in the PKD1 gene will improve the accuracy of linkage studies in ADPKD families.

• Peral B, Ong AC, San Millan JL, Gamble V, Rees L, Harris PC
• A stable, nonsense mutation associated with a case of infantile onset polycystic kidney disease 1 (PKD1).
• Hum Mol Genet. 1996; 5: 539-42
• Display abstract

• Autosomal dominant polycystic kidney disease (ADPKD) is the most common single gene disorder resulting in renal failure. It is generally an adult onset disease, but rarely, cases of severe childhood polycystic disease arise in ADPKD families. The clear clinical anticipation in these pedigrees has led to the suggestion that the mutation may be an unstable trinucleotide repeat. We have now identified a nonsense mutation, Tyr3818Stop, in one such family (P117) within the major ADPKD gene, polycystic kidney disease 1 (PKD1). The mutation is shown to be a de novo change in the father, and of grandpaternal origin. PKD1 manifests as typical adult onset disease in the father, but is seen as severe disease, detected as enlarged polycystic kidneys in utero, in one of a pair of dizygotic twins; the other twin has the mutation but no evidence of cysts, consistent with an adult onset disease course. The finding of the same stable mutation associated with very different disease severity in this family indicates that phenotypic variation in PKD1 is not due to a dynamic mutation. It seems most likely that a small number of modifying factors may radically affect the course of disease in PKD1; identification of such factors will have important prognostic implications in this disorder.

• Peral B et al.
• Screening the 3' region of the polycystic kidney disease 1 (PKD1) gene reveals six novel mutations.
• Am J Hum Genet. 1996; 58: 86-96
• Display abstract

• Recently, the gene for the most common form of autosomal dominant polycystic kidney disease (ADPKD), PKD1 (polycystic kidney disease 1), has been fully characterized and shown to encode an integral membrane protein, polycystin, involved in cell-cell and/or cell-matrix interactions. Study of the PKD1 gene has been complicated because most of the gene lies in a genomic region reiterated several times elsewhere on the same chromosome, and consequently only seven mutations have been described so far. Here we report a systematic screen covering approximately 80% of the approximately 2.75 kb of translated transcript that is encoded by single-copy DNA. We have identified and characterized six novel mutations that, together with the previously described changes, amount to a detection rate of 10%-15% in the population studied. The newly described mutations are two deletions, an insertion of a T-nucleotide causing a frame shift, two single-base-pair substitutions resulting in premature stop codons, and a G-->C transversion that may be a missense mutation. These results have important implications for genetic diagnosis of PKD1 because they indicate that the majority of mutations lie within the duplicated area, which is difficult to study. The regions of polycystin removed in each mutation so far described are assessed for their functional significance; an area disrupted by two new small in-frame changes is highlighted. PKD1 mutations are contrasted with those in the PKD1/TSC2 contiguous-gene syndrome, and the likely mutational mechanism in PKD1 is considered.

• Grantham JJ
• The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: recent advances.
• Am J Kidney Dis. 1996; 28: 788-803
• Display abstract

• Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in at least three different genes: PKD1, PKD2, and PKD3. ADPKD1 is an inherited disorder that has led to the discovery of a novel protein, polycystin. Polycystin, a 460 kd protein with a host of domains implicating a potential role in cell-cell and cell-matrix regulation, is encoded by a 52 kb gene with a 14 kb mRNA. The PKD2 protein is also large (110 kd) and is thought to interact with polycystin. ADPKD1 is caused by mutated DNA that encodes an abnormal form of polycystin. Polycystin appears to have a normal role in the differentiation of epithelial cells, and when defective, these cells fail to maturate fully. These incompletely differentiated cells proliferate abnormally and express altered amounts of otherwise normal electrolyte transport proteins that result in excessive secretion of solute and fluid into the cysts. The proliferation of the cells and the associated apoptosis, and the secretion of the fluid into the cysts created by the enlarging tubule segments appear to be regulated by growth factors, hormones, and cytokines that can alter the extent to which the disease is clinically expressed among individuals. The formation of the cysts is associated with complex changes in the extracellular matrix of the kidneys and other organs that may be directly or indirectly tied to mutated polycystin. The summation of these pathogenetic elements leads to renal interstitial infiltration, with monocytes, macrophages, and fibroblasts culminating in fibrosis and progressive loss of renal function. The modem understanding of cyst pathogenesis opens opportunities to develop treatments that may diminish or halt altogether the progression of this disease.

• Wilson PD, Norman JT, Kuo NT, Burrow CR
• Abnormalities in extracellular matrix regulation in autosomal dominant polycystic kidney disease.
• Contrib Nephrol. 1996; 118: 126-34

• Qian F, Watnick TJ, Onuchic LF, Germino GG
• The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I.
• Cell. 1996; 87: 979-87
• Display abstract

• Autosomal dominant polycystic kidney disease (ADPKD) is a common disease and an important cause of renal failure. It is characterized by considerable intrafamilial phenotypic variation and focal cyst formation. To elucidate the molecular basis for these observations, we have developed a novel method for isolating renal cystic epithelia from single cysts and have used it to show that individual renal cysts in ADPKD are monoclonal. Loss of heterozygosity was discovered within a subset of cysts for two closely linked polymorphic markers located within the PKD1 gene. Genetic analysis revealed that it was the normal haplotype that was lost. This study provides a molecular explanation for the focal nature of cyst formation and a probable mechanism whereby mutations cause disease. The high rate at which "second hits" must occur to account for the large number of cysts observed suggests that unique structural features of the PKD1 gene may be responsible for its mutability.

• Peters DJ et al.
• Adult, fetal, and polycystic kidney expression of polycystin, the polycystic kidney disease-1 gene product.
• Lab Invest. 1996; 75: 221-30
• Display abstract

• The polycystic kidney disease-1 gene, which is mutated in the majority of patients with autosomal dominant polycystic kidney disease, has been identified. The protein encoded by this gene, polycystin, has no homology with any gene known thus far. To gain more insight into the function of polycystin, we raised antibodies against synthetic peptides and a fusion protein corresponding to the sequence of two different fragments of polycystin. Two of the antibodies were capable of immunoprecipitating an in vitro transcription and translation product corresponding to a fragment of polycystin. In the cyst-lining epithelium of polycystic kidney disease-1 patients, a strong staining was observed. In normal adult and embryonic kidney tissues, expression was seen in the epithelium of all tubular structures and in the glomerular parietal and visceral epithelium (podocytes), although the podocytes were mainly recognized on cryosections and not on paraffin sections. A double-labeled immunofluorescence with one of the polycystin antibodies and the monoclonal antibody 8G8 ascertained that within the glomerular tuft podocytes were recognized.

• Roelfsema JH, Breuning MH
• The long walk toward the PKD1 gene. The European PKD1 Consortium.
• Adv Nephrol Necker Hosp. 1996; 25: 131-45

• Van Raay TJ, Connors TD, Klinger KW, Landes GM, Burn TC
• A novel ribosomal protein L3-like gene (RPL3L) maps to the autosomal dominant polycystic kidney disease gene region.
• Genomics. 1996; 37: 172-6
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• A full-length cDNA encoding a novel ribosomal protein L3 gene was isolated and sequenced. The deduced protein sequence is 407 amino acids long and shows 77% identity to other known mammalian ribosomal protein L3 genes, which are themselves highly conserved. Southern blot analysis of human genomic DNA suggests that this novel gene is single copy. While the previously identified human ribosomal protein L3 gene has ubiquitous expression in all tissues surveyed, the novel gene described herein is strongly expressed in skeletal muscle and heart tissue, with low levels of expression in the pancreas. This novel gene, RPL3L, is located in a gene-rich region near the PKD1 and TSC2 genes on chromosome 16p13.3.

• Mochizuki T et al.
• PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.
• Science. 1996; 272: 1339-42
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• A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.

• Harris PC
• Identification of a gene for autosomal dominant polycystic kidney disease: implications for understanding the pathogenesis and treatment of the disease.
• Nephrol Dial Transplant. 1996; 11: 258-62

• Turco AE, Clementi M, Rossetti S, Tenconi R, Pignatti PF
• An Italian family with autosomal dominant polycystic kidney disease unlinked to either the PKD1 or PKD2 gene.
• Am J Kidney Dis. 1996; 28: 759-61
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• We describe a family with autosomal dominant polycystic kidney disease in which molecular typing with closely linked markers for the PKD1 and PKD2 genes indicated absence of linkage. Thus, a third still unknown locus appears likely to be involved in disease development. This is the fourth "PKD3-linked" family described to date and the first from Italy.

• Schneider MC
• Advances in polycystic kidney disease.
• Mol Med Today. 1996; 2: 70-5
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• Until recently, the nature of the molecules involved in inherited cystic disease of the kidney remained unknown. These diseases are characterized by the development of multiple abnormal fluid-filled sacs or dilations in the kidney parenchyma, often leading to significant renal failure. The recent characterization of the PKD1 gene product and of other genes involved in murine polycystic models underscores the complexity of the pathways that lead to renal cystic disease.

• Rossetti S et al.
• Autosomal dominant polycystic kidney disease (ADPKD) in an Italian family carrying a novel nonsense mutation and two missense changes in exons 44 and 45 of the PKD1 Gene.
• Am J Med Genet. 1996; 65: 155-9
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• Sixty-seven Italian patients with autosomal dominant polycystic kidney disease (ADPKD) were screened for mutations in the 3' unique region of the PKD1 gene, using heteroduplex DNA analysis. Novel aberrant bands were detected in 3 patients from the same family. DNA sequencing showed a C to T transition in exon 44 (C12269T), resulting in a premature stop codon (R4020X), predicted to impair the synthesis of the putative intracytoplasmic C-terminus tail of the PKD1 protein, polycystin. The mutation also generates a novel DdeI restriction site, and the abnormal restriction pattern was observed both on genomic DNA and on cDNA from the affected relatives, indicating that this is indeed the pathogenetic molecular lesion. Reverse transcriptase-polymerase chain reaction (RT-PCR) performed on lymphocyte mRNA showed that the mutant transcript is normally present and stable. No aberrantly spliced mRNAs were detected. Interestingly, the mutant PKD1 chromosome in this family also bears two missense mutations downstream (A12341G and C12384T), not found in the other ADPKD families studied.

• Schrick JJ et al.
• Characterization of the human homologue of the mouse Tg737 candidate polycystic kidney disease gene.
• Hum Mol Genet. 1995; 4: 559-67
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• We previously identified a gene from the mutant locus in a new mouse mutation that causes recessive polycystic kidney disease. Here we describe the cloning, characterization and mapping of the homologous human gene. The human and mouse genes are 95% identical at the predicted amino acid sequence level, and both genes encode a putative protein that contains a tetratricopeptide repeat motif. The human gene, called hTg737, is expressed with a broad tissue distribution that includes the the kidney and liver, and gives rise to a 2.9 kb mRNA. The gene contains 26 exons and spans a genomic region greater than 100 kb. Chromosome mapping experiments revealed that the hTg737 gene maps near the centromere on the long arm of human chromosome 13, at position 13q12.1. While this gene does not map to the primary locus that has been identified for ARPKD in humans, it may represent a candidate gene for other recessive renal disorders that have yet to be mapped.

• Harris PC, Germino G, Klinger K, Landes G, van Adelsberg J
• The PKD1 gene product.
• Nat Med. 1995; 1: 493-493

• Dimitrakov D
• Modern clinical, diagnostic and therapeutic approaches in characterization of the autosomal dominant polycystic kidney disease.
• Folia Med (Plovdiv). 1995; 37: 40-40

• Pound SE et al.
• Haplotype analysis in autosomal dominant polycystic kidney disease.
• J Med Genet. 1995; 32: 208-12
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• Haplotype analysis was performed in 35 autosomal dominant polycystic kidney disease (ADPKD) families typed with 13 markers close to the PKD1 locus. The identification of recombinants close to the PKD1 gene on chromosome 16p indicates that PKD1 lies between CMM65 distally and 26-6 proximally. In addition, three unlinked (PKD2) families and two families with potential new mutation were identified.

• Grantham JJ
• Polycystic kidney disease--there goes the neighborhood.
• N Engl J Med. 1995; 333: 56-7

• Grantham JJ
• Pathogenesis of renal cysts in dominantly inherited polycystic kidney disease.
• Contrib Nephrol. 1995; 115: 16-9

• Rondeau E
• [Polycystic kidney: complete structure of the PKD1 gene and its protein]
• Nephrologie. 1995; 16: 338-9

• Harris PC, Ward CJ, Peral B, Hughes J
• Polycystic kidney disease. 1: Identification and analysis of the primary defect.
• J Am Soc Nephrol. 1995; 6: 1125-33
• Display abstract

• The identification of the primary defect in autosomal dominant polycystic kidney disease (ADPKD) by biochemical methods has proved difficult because of the complexity of the cystic kidney. However, by the use of the genetic method of positional cloning, a gene accounting for approximately 85% of ADPKD, PKD1, has now been identified in the chromosome region 16p13.3. Its exact location was pinpointed because it was bisected by a chromosome translocation; members with the balanced exchange had PKD1. The PKD1 gene encodes an approximately 14-kb transcript, but full characterization was complicated, because most of the gene lies in a genomic region that is duplicated elsewhere on chromosome 16; the duplicate area encodes three genes with substantial homology to PKD1. At present, only seven mutations of PKD1 have been characterized and these are clustered in the nonduplicated, 3' end of the gene. However, a number of patients with large deletions of the PKD1 and adjacent tuberous sclerosis 2 (TSC2) genes, who have tuberous sclerosis and severe childhood-onset polycystic kidney disease, have also been described. Recently, the entire sequence of the PKD1 transcript and the genomic region containing the gene have been determined. The PKD1 gene covers approximately 52 kb of genomic DNA and is divided into 46 exons. The transcript is approximately 14.15 kb, and the predicted protein polycystin is 4302/3 amino acids with a calculated mass of approximately 460 kd. Polycystin contains several distinctive extracellular domains, including a flank-leucine rich repeat-flank domain, a C-type lectin, 16 approximately 85-amino-acid units that are similar to immunoglobulin repeats, four fibronectin Type III-related domains, and a low-density lipoprotein A domain. The C-terminal third of the protein has multiple hydrophobic regions, and modeling of this region suggests the presence of many transmembrane domains and a cytoplasmic C terminus. Hence, polycystin is probably an integral membrane protein with multiple extracellular domains that are involved in cell-cell and/or cell-matrix interactions. The ADPKD phenotype suggests that polycystin may play a role in cell-matrix communication, which is important for normal basement membrane production and for controlling cellular differentiation.

• Van Adelsberg JS, Frank D
• The PKD1 gene produces a developmentally regulated protein in mesenchyme and vasculature.
• Nat Med. 1995; 1: 359-64
• Display abstract

• Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human genetic diseases. In addition to polycystic kidneys, the disease can cause cystic changes in liver and other organs, cardiac valvular insufficiency and cerebral arterial aneurysms. Using antibodies raised against the predicted gene product of PKD1, which is mutated in about 85% of ADPKD cases, we show that PKD1 is a 530-kD protein localized to the extracellular matrix of kidney, liver and cerebral blood vessels. We discovered that the PKD1 protein was highly expressed in the mesenchyme of developing kidney and liver, transiently localized in the developing glomerulus and juxtaglomerular apparatus and restricted to perivascular, extraglomerular areas in adult renal cortex. These data suggest that the PKD1 protein plays a role in renal and hepatic morphogenesis.

• Ravine D, Becker GJ
• Newly diagnosed polycystic kidney disease: what to do with the family?
• Aust N Z J Med. 1995; 25: 469-71

• Dimitrakov D
• Molecular and genetic studies of 22 Bulgarian families with autosomal dominant polycystic kidney disease (ADPKD). Extrarenal clinical manifestations of ADPKD compared with data from DNA analysis.
• Folia Med (Plovdiv). 1995; 37: 41-2

• Snarey A et al.
• Linkage disequilibrium in the region of the autosomal dominant polycystic kidney disease gene (PKD1).
• Am J Hum Genet. 1994; 55: 365-71
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• The gene for autosomal dominant polycystic kidney disease (PKD1) is located on chromosome 16p, between the flanking markers D16S84 and D16S125 (26.6prox). This region is 750 kb long and has been cloned. We have looked at the association of 10 polymorphic markers from the region, with the disease and with each other. This was done in a set of Scottish families that had previously shown association with D16S94, a marker proximal to the PKD1 region. We report significant association between two CA repeat markers and the disease but have not found evidence for a single founder haplotype in these families, indicating the presence of several mutations in this population. Our results favor a location of the PKD1 gene in the proximal part of the candidate region.

• Kraus B et al.
• A novel cyclin gene (CCNF) in the region of the polycystic kidney disease gene (PKD1).
• Genomics. 1994; 24: 27-33
• Display abstract

• The major locus for autosomal dominant polycystic kidney disease (PKD1) is located in a gene-rich region on chromosome 16p13.3. Recently the identification of the gene responsible for PKD1 has been described. While searching for candidate genes in this region, we isolated a new member of the cyclin family. We have characterized the transcript by sequencing, determination of the exon intron boundaries, and Northern blot analysis. Cyclin F is related to A- and B-type cyclins by sequence, but its function is unknown.

• Zerres K, Mucher G, Rudnik-Schoneborn S
• Autosomal recessive polycystic kidney disease does not map to the second gene locus for autosomal dominant polycystic kidney disease on chromosome 4.
• Hum Genet. 1994; 93: 697-8
• Display abstract

• Linkage analysis in 19 families with autosomal recessive polycystic kidney disease (ARPKD) has shown that ARPKD is not linked to the recently assigned second gene locus for autosomal dominant polycystic kidney disease (ADPKD) on chromosome 4q (PKD2). Thus, there is strong evidence that ADPKD and ARPKD have different gene loci.

• Weinstat-Saslow DL, Germino GG, Somlo S, Reeders ST
• A transducin-like gene maps to the autosomal dominant polycystic kidney disease gene region.
• Genomics. 1993; 18: 709-11
• Display abstract

• A novel human gene (sazD) that maps to the autosomal dominant polycystic kidney disease region shares sequence similarity with members of the beta-transducin superfamily. The cDNA sazD-c predicts an approximately 58-kDa protein (sazD) with seven internal repeats, similar to the WD-40 motif of the transducin family. The size of this protein family has been expanding rapidly; however, neither the structure nor the function of this repeated motif is known. Preliminary data do not suggest that sazD is mutated in patients with polycystic kidney disease.

• Gabow PA
• Autosomal dominant polycystic kidney disease.
• N Engl J Med. 1993; 329: 332-42

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