Secondary literature sources for ALBUMIN
The following references were automatically generated.
- Vorum H
- Reversible ligand binding to human serum albumin. Theoretical and clinical aspects.
- Dan Med Bull. 1999; 46: 379-99
- Gibbs PE, Witke WF, Dugaiczyk A
- The molecular clock runs at different rates among closely related members of a gene family.
- J Mol Evol. 1998; 46: 552-61
- Display abstract
The serum albumin gene family is composed of four members that have arisen by a series of duplications from a common ancestor. From sequence differences between members of the gene family, we infer that a gene duplication some 580 Myr ago gave rise to the vitamin D-binding protein (DBP) gene and a second lineage, which reduplicated about 295 Myr ago to give the albumin (ALB) gene and a common precursor to alpha-fetoprotein (AFP) and alpha-albumin (ALF). This precursor itself duplicated about 250 Myr ago, giving rise to the youngest family members, AFP and ALF. It should be possible to correlate these dates with the phylogenetic distribution of members of the gene family among different species. All four genes are found in mammals, but AFP and ALF are not found in amphibia, which diverged from reptiles about 360 Myr ago, before the divergence of the AFP-ALF progenitor from albumin. Although individual family members display an approximate clock-like evolution, there are significant deviations-the rates of divergence for AFP differ by a factor of 7, the rates for ALB differ by a factor of 2.1. Since the progenitor of this gene family itself arose by triplication of a smaller gene, the rates of evolution of individual domains were also calculated and were shown to vary within and between family members. The great variation in the rates of the molecular clock raises questions concerning whether it can be used to infer evolutionary time from contemporary sequence differences.
- Wang X, Xie H
- [Study of alpha-fetoprotein]
- Zhonghua Yi Xue Za Zhi. 1998; 78: 723-4
- Mal F, Girard P, Gayet B
- [Congenital high increase of serum alpha-fetoprotein: case of a family]
- Gastroenterol Clin Biol. 1997; 21: 903-903
- Nishio H, Heiskanen M, Palotie A, Belanger L, Dugaiczyk A
- Tandem arrangement of the human serum albumin multigene family in the sub-centromeric region of 4q: evolution and chromosomal direction of transcription.
- J Mol Biol. 1996; 259: 113-9
- Display abstract
The albumin gene family is comprised of four genes encoding: serum albumin (ALB), alpha-fetoprotein (AFP), alpha-albumin (ALF), and vitamin D-binding protein (DBP; also known as GC). The genes are regulated developmentally, expressed in the liver, and the proteins are secreted into the bloodstream. The GC gene, and the tandemly linked ALB and AFP genes, have been previously localized to human chromosome 4q11-13. Using techniques of fluorescence in situ hybridization to chromatin fibres, chromosome walking and DNA sequencing of genomic clones, we now report on the chromosomal location of the ALF gene and the organization of the entire gene family. The four genes are tandemly linked in the 4q sub-centromeric region: 5'ALB-5'AFP-5'ALF-5'GC3'-centromere, and hence are transcribed in the same, centromere-bound, direction. The linear arrangement of the four genes along the chromosome is not correlated with their temporal expression in the human ontogeny. It appears that GC is very close (and may be the gene proximal) to the centromere. The linear chromosomal arrangement of the four genes and the structural differences between them are congruent with the following evolutionary divergence of the gene family. Starting with the first duplication of an ancestral progenitor gene, a single evolutionary line led to the contemporary GC, leaving ALB/AFP/ALF on the other line of descent. The second duplication occurred in this ALB lineage, giving rise to ALB and the AFP/ALF progenitor, and the third, most recent one, gave rise to the AFP-ALF pair.
- Nishio H, Dugaiczyk A
- Complete structure of the human alpha-albumin gene, a new member of the serum albumin multigene family.
- Proc Natl Acad Sci U S A. 1996; 93: 7557-61
- Display abstract
The nucleotide sequence of the human alpha-albumin gene, including 887 bp of the 5'-flanking region and 1311 bp of the 3-flanking region (24,454 in total), was determined from three overlapping lambda phage clones. The sequence spans 22,256 bp from the cap site to the polyadenylylation site, revealing a gene structure of 15 exons separated by 14 introns. The methionine initiation codon ATG is within exon 1; the termination codon TGA is within exon 14. Exon 15 is entirely untranslated and contains the polyadenylylation signal AATAAA. The deduced polypeptide chain is composed of a 21-amino-acid leader peptide, followed by 578 amino acids of the mature protein. There are seven repetitive DNA elements (Alu and Kpn) in the introns and 3-flanking region. The sizes of the 15 alpha-albumin exons match closely those of the albumin, alpha-fetoprotein, and vitamin D-binding protein genes. The exons are symmetrically placed within the three domains of the individual proteins, and they share a characteristic codon splitting pattern that is conserved among members of the gene family. The results provide strong evidence that alpha-albumin belongs to, and most likely completes with, the serum albumin gene family. Based on structural similarity, alpha-albumin appears to be most closely related to alpha-fetoprotein. The complete structure of this family of four tandemly linked genes provides a well-characterized approximately 200 kb locus in the 4q subcentromeric region of the human genome.
- Brown MA, Carne A, Daugherty CH, Chambers GK
- Identification of a 130-kDa albumin in tuatara (Sphenodon) and detection of a novel albumin polymorphism.
- Biochem Genet. 1995; 33: 189-204
- Display abstract
Electrophoretic, immunochemical, and protein sequence analyses were performed on plasma albumin of the tuatara (Sphenodon), a rare reptile endemic to New Zealand. The analyses revealed that, unlike other terrestrial vertebrates, tuatara do not seem to possess a 60- to 75-kDa plasma albumin. The common form of plasma albumin in this genus has an apparent molecular mass of 130 kDa, making it by far the largest albumin reported for any terrestrial vertebrate. Starch gel electrophoresis of samples from tuatara on 24 of the 30 islands inhabited by this genus resolved two forms of the 130-kDa albumin (albumins A and C). A third albumin of approximately 170 kDa (albumin B), reflecting a novel alloalbuminemia, was found in tuatara in three geographically isolated populations. Albumin A appears to be restricted to populations at the southern extremity of the tuatara's distribution, while albumin C was found in all but four (southern) populations. Possible explanations for the origin and distribution of these albumins are discussed.
- Belanger L, Roy S, Allard D
- New albumin gene 3' adjacent to the alpha 1-fetoprotein locus.
- J Biol Chem. 1994; 269: 5481-4
- Display abstract
The albumin multigene family encodes proteins synthesized in the liver and secreted in the serum to fulfill ligand-carrier functions. The albumin (ALB), alpha 1-fetoprotein (AFP), and vitamin D-binding protein genes are syntenic, the ALB and AFP genes are organized in tandem, and the AFP gene is selectively expressed in the fetal liver. We now report the existence of a fourth member of the albumin gene family, located 10 kilobases downstream from the AFP locus. The new gene, named alpha-albumin (alpha ALB), is selectively expressed in the liver at late stages of development. The alpha ALB mRNA sequence encodes a predicted secreted protein with the typical triple domain disulfide cross-linked structure. Comparisons of coding and promoter sequences suggest that alpha ALB could be a phylogenetic intermediate between the ALB and AFP genes. The developmental switch between alpha ALB gene activation and AFP gene repression suggests new regulatory interplays at the albumin locus and adult stage-specific ligand binding functions carried out by the alpha ALB gene product.
- Liu ZY, Liu GT
- [Regulation of alpha-fetoprotein gene expression]
- Sheng Li Ke Xue Jin Zhan. 1994; 25: 161-4
- Gibbs PE, Dugaiczyk A
- Reading the molecular clock from the decay of internal symmetry of a gene.
- Proc Natl Acad Sci U S A. 1994; 91: 3413-7
- Display abstract
The closely related serum albumin, alpha-fetoprotein, and vitamin D-binding proteins are derived from a common ancestor, which itself was the result of a triplication of an ancestral gene. We have aligned the sequences of these proteins against themselves to assess the degree to which the ancestral 3-fold symmetry has been retained; in a dot plot, relics of the molecular symmetry appear as a series of alignments parallel to the main diagonal. The decay of internal symmetry reflects the rate of change of a gene in a single line of evolutionary descent. We examined 11 serum albumins, 2 ceruloplasmins, 3 alpha-fetoproteins, and 3 vitamin D-binding proteins. We have found that ceruloplasmin evolves at the same rate in human and rat, whereas albumin, alpha-fetoprotein, and vitamin D-binding protein evolve at different rates. The human genes had the highest alignment scores, indicating the most preserved ancestral features. We conclude that the molecular clock may run at different rates for the same gene in different species.
- Witke WF, Gibbs PE, Zielinski R, Yang F, Bowman BH, Dugaiczyk A
- Complete structure of the human Gc gene: differences and similarities between members of the albumin gene family.
- Genomics. 1993; 16: 751-4
- Display abstract
The sequence of the human Gc gene, including 4228 base pairs of the 5'-flanking region and 8514 base pairs of the 3' flanking region (55,136 in total), was determined from five overlapping lambda phage clones. The sequence spans 42,394 base pairs from the cap site to the polyadenylation site, and it reveals that the gene is composed of 13 exons, which are symmetrically placed within the three domains of the Gc protein. The first exon is partially untranslated, as is exon 12, which contains the termination codon TAG. Exon 13 is entirely untranslated, but contains the polyadenylation signal AATAAA. Ten central introns split the coding sequence between codon positions 2 and 3 and between codon positions 3 and 1 in an alternating pattern, exactly as has been observed in the structure of the albumin and alpha-fetoprotein genes. The Gc gene has several distinctive features which set it apart from the other members of the family. First, the gene is smaller by two exons, which results in a protein some 130 amino acids shorter than albumin or AFP. This decrease in size may result from the loss of two internal exons during the evolutionary history of the Gc gene. Second, exons 6, 8, 9, and 11 are smaller than their counterparts in albumin or AFP by a total of 8 codons (1, 4, 1, and 2, respectively). Although the mRNA and protein expressed from the Gc gene are significantly smaller, the gene itself is about 2.5 times larger than the other genes of the family.(ABSTRACT TRUNCATED AT 250 WORDS)
- McVey JH et al.
- A G-->A substitution in an HNF I binding site in the human alpha-fetoprotein gene is associated with hereditary persistence of alpha-fetoprotein (HPAFP).
- Hum Mol Genet. 1993; 2: 379-84
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A family displaying hereditary persistence of alpha-fetoprotein (HPAFP) in adult life was detected in an antenatal screening programme for spina bifida. RFLP linkage analysis shows that the trait is linked with the albumin-AFP locus. The molecular mechanism responsible for the post-natal repression of the AFP gene is unknown. We wished to determine the molecular mechanism underlying HPAFP in this family. Sequence analysis of the 5'-flanking sequences of their gene revealed a GA substitution at position -119 associated with the trait. This substitution occurs in a potential HNF I binding site, and increases the similarity of the sequence to a consensus HNF I recognition site. In a competitive gel retardation assay the mutant sequence binds HNF I alpha more tightly than the wild type sequence. Furthermore, 5'-flanking sequences of the human AFP gene containing the G-->A substitution direct a higher level of CAT expression in transfected human hepatoma cells than the wild type sequences. We conclude that the G-->A substitution at position -119 of the AFP gene is the mutation causing HPAFP in this family. These results highlight the importance of this HNF I binding site in the developmental regulation of the AFP gene.
- Braun A, Kofler A, Morawietz S, Cleve H
- Sequence and organization of the human vitamin D-binding protein gene.
- Biochim Biophys Acta. 1993; 1216: 385-94
- Display abstract
The structure and organization of the human vitamin D-binding protein (DBP) gene has been determined. The gene is composed of 13 exons and 12 intervening sequences. With the help of the polymerase chain reaction (PCR) introns were amplified using exon-specific oligonucleotide primers, and were sequenced after subcloning; the exon/intron borders were determined. The introns 2, 5, 7, 9 and 10 were sequenced completely; the introns 1, 3, 4, 6, 8, 11 and 12 were sequenced in part. We designed intron-specific primers for the amplification of each exon by the PCR-method. This permits the analysis of mutational and function-related sites. By comparison with the genes for human albumin and alpha-fetoprotein the gene for DBP/GC is confirmed as a member of this multigene family. The location of the introns in the coding region of the human DBP-gene is identical with the position of the introns in the rat DBP-gene.
- Bilir BM
- Lessons from the repression of the alpha-fetoprotein gene in the adult liver.
- Hepatology. 1993; 18: 1009-11
- Sorkina DA
- [Molecular basis of the origin of serum albumin (review of the literature)]
- Vopr Med Khim. 1990; 36: 2-5
- Byrnes L, Gannon F
- Atlantic salmon (Salmo salar) serum albumin: cDNA sequence, evolution, and tissue expression.
- DNA Cell Biol. 1990; 9: 647-55
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Atlantic salmon serum albumin is one of the most abundant proteins in salmon liver, representing 1.6% of all clones in a cDNA library made from salmon liver RNA. The DNA from a number of clones was sequenced to reveal an open reading frame of 1,827 bases encoding a 608-amino-acid protein. The sequenced 5' untranslated region is 69 bases long and the 3' untranslated region contains two putative polyadenylation signals and poly(A) tail. Sequence analysis of different clones indicates the presence of a second cDNA for salmon serum albumin. Multiple alignments of salmon serum albumin deduced amino acid sequence with Xenopus laevis, rat, bovine, and human serum albumins shows significant conservation of cysteine residues. The triple domain structure of serum albumin proteins is maintained. Unlike mammalian systems where serum albumin expression appears to be specific to liver only, salmon serum albumin is expressed in muscle also.
- Baker ME
- Conservation of amino acid sequences in albumin: is albumin an essential protein?
- Mol Biol Evol. 1989; 6: 321-3
- Jose M, Tratner I, Poiret M, Nahon JL, Danan JL, Sala-Trepat JM
- The organization of repetitive sequences in the albumin and alpha-fetoprotein gene loci in the rat.
- Mol Gen Genet. 1989; 215: 225-30
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The distribution of middle repetitive sequences in the genic and extragenic regions of the rat albumin and alpha-fetoprotein genes was analyzed. Their presence was determined by probing Southern blots of restriction fragments of albumin and alpha-fetoprotein genomic subclones with 32P-labeled total rat DNA. Repetitive sequences were detected in both genes. They were classified as weak, moderate and intense hybridizing elements according to the intensity of hybridization. Weak repetitive sequences were characterized as dG.dT repeats by using 32P-labeled poly-(dG.dT)(dC.dA) oligomer probe. They occurred in 5' and 3' extragenic regions of the two genes and in introns 4 and 5 of the albumin gene. The moderate repetitive sequence present in intron 6 of the albumin gene was identified as the rat SINES element. 4D12. The intense repetitive sequence, localized in the 3' non-coding region of the albumin gene, corresponded to the terminal segment of a rat high repeat long interspersed DNA family, L1Rn. 4D12 and L1Rn sequences were also scattered throughout the alpha-fetoprotein locus as moderate and intense repetitive elements, respectively, but their distribution was different from that of the albumin genomic region. These results indicate that repetitive sequences invaded the two loci in a non-conservative manner.
- Baker ME
- Evolution of estrogen binding in rat and mouse alpha-fetoprotein.
- Bioessays. 1989; 11: 112-4
- Haefliger DN, Moskaitis JE, Schoenberg DR, Wahli W
- Amphibian albumins as members of the albumin, alpha-fetoprotein, vitamin D-binding protein multigene family.
- J Mol Evol. 1989; 29: 344-54
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The Xenopus laevis 68-kd and 74-kd albumin amino acid sequences are examined with respect to their relationship to the other known members of the albumin/alpha-fetoprotein/vitamin D-binding protein gene family. Each of the three members of this family presents a unique pattern of conserved regions indicating a differential selective pressure related to specific functional characteristics. Furthermore, an evolutionary tree of these genes was deduced from the divergence times calculated from direct nucleotide sequence comparisons of individual gene pairs. These calculations indicate that the vitamin D-binding protein/albumin separation occurred 560-600 million years (Myr) ago and the albumin/alpha-fetoprotein divergence 280 Myr ago. This observation leads to the hypothesis according to which the albumin/alpha-fetoprotein gene duplication occurred shortly after the amphibian/reptile separation. Consequently, and unlike mammals, amphibians and fishes should lack an alpha-fetoprotein in their serum at larval stages, which is consistent with a recent analysis of serum proteins in Xenopus laevis larvae. This hypothesis now will have to be tested further in additional lower vertebrates.
- Sorokina DA
- [Structural aspects of the transport function of serum albumin (review)]
- Vopr Med Khim. 1988; 34: 8-16
- Baker ME
- Evolution of alpha-fetoprotein: sequence comparisons among AFP species and with albumin species.
- Tumour Biol. 1988; 9: 123-36
- Display abstract
Alpha-fetoprotein (AFP) and albumin are related proteins, which contain about 585 amino acid residues that are organized in a characteristic structure of 3 homologous domains of about 195 amino acid residues. We have compared the domains of mouse, rat, and human AFP and rat, bovine, and human albumin using computer programs designed to quantify relationships between proteins. The comparisons of corresponding domains of the AFPs (e.g. domain I of rat and human AFP) reveal that each domain is well conserved. Similar results were found for the comparisons of corresponding domains in the albumins. In contrast, there was much less similarity between corresponding domains of albumin and AFP. These comparisons between AFP and albumin revealed that: (1) the amino acid sequences in domain III, which is at their carboxy terminus, are most conserved, and (2) the amino acid sequences in domain I, which is at their amino terminus, are least conserved. This suggests that there are differences in the constraints on amino acid substitutions among the domains of AFP and albumin during the approximately 400 million years since they diverged from a common ancestor. Also, computer studies revealed that there are substantial differences between domains I, II, and III in each AFP and albumin species, which indicates that these domains are significantly different from their approximately 195 residue ancestral domain. Finally, we find that mouse and rat AFP are more dissimilar to the albumins than is human AFP. Overall, our computer analyses indicate that AFP and albumin can be considered to be composed of distinct, but related, approximately 195 residue proteins, each of which could differ in some of their properties; for example, the binding of fatty acids.
- Ruffner DE, Sprung CN, Minghetti PP, Gibbs PE, Dugaiczyk A
- Invasion of the human albumin-alpha-fetoprotein gene family by Alu, Kpn, and two novel repetitive DNA elements.
- Mol Biol Evol. 1987; 4: 1-9
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The human albumin-alpha-fetoprotein genomic domain contains 13 repetitive DNA elements randomly distributed throughout the symmetrical structures of these genes. These repeated sequences are located at different sites within the two genes. The human albumin gene contains five Alu elements within four of its 14 intervening sequences. Two of these repeats are located in intron 2, and the remaining three are located in introns 7, 8, and 11. The human alpha-fetoprotein gene contains three of these Alu elements, one in intron 4 and the remaining two in the 3'-untranslated region. In addition, the human alpha-fetoprotein gene contains a Kpn repeat and two classes of novel repeats that are absent from the human albumin gene. Six of the Alu elements within the two genes are bound by short direct repeats that harbor five base substitutions in 120 possible positions (60 bp times 2 termini). The absence of Alu repeats from analogous positions in rodents indicates that these repeats invaded the albumin-alpha-fetoprotein domain less than 85 Myr ago (the time of mammalian radiation). Furthermore, considering the conservation of terminal repeats flanking the Alu sequences of the albumin-alpha-fetoprotein domain (0.042 changes per site), we submit that the average time of Alu insertion into this gene family could have been as recently as 15-30 Myr ago.
- Gibbs PE, Zielinski R, Boyd C, Dugaiczyk A
- Structure, polymorphism, and novel repeated DNA elements revealed by a complete sequence of the human alpha-fetoprotein gene.
- Biochemistry. 1987; 26: 1332-43
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The human alpha-fetoprotein gene spans 19,489 base pairs from the putative "Cap" site to the polyadenylation site. It is composed of 15 exons separated by 14 introns, which are symmetrically placed within the three domains of alpha-fetoprotein. In the 5' region, a putative TATAAA box is at position -21, and a variant sequence, CCAAC, of the common CAT box is at -65. Enhancer core sequences GTGGTTTAAAG are found in introns 3 and 4, and several copies of glucocorticoid response sequences AGATACAGTA are found on the template strand of the gene. There are six polymorphic sites within 4690 base pairs of contiguous DNA derived from two allelic alpha-fetoprotein genes. This amounts to a measured polymorphic frequency of 0.13%, or 6.4 X 10(-4)/site, which is about 5-10 times lower than values estimated from studies on polymorphic restriction sites in other regions of the human genome. There are four types of repetitive sequence elements in the introns and flanking regions of the human alpha-fetoprotein gene. At least one of these is apparently a novel structure (designated Xba) and is found as a pair of direct repeats, with one copy in intron 7 and the other in intron 8. It is conceivable that within the last 2 million years the copy in intron 8 gave rise to the repeat in intron 7. Their present location on both sides of exon 8 gives these sequences a potential for disrupting the functional integrity of the gene in the event of an unequal crossover between them. There are three Alu elements, one of which is in intron 4; the others are located in the 3' flanking region. A solitary Kpn repeat is found in intron 3. The Xba and Kpn repeats were only detected by complete sequencing of the introns. Neither X, Xba, nor Kpn elements are present in the related human albumin gene, whereas Alu's are present in different positions. From phylogenetic evidence, it appears that Alu elements were inserted into the alpha-fetoprotein gene at some time postdating the mammalian radiation 85 million years ago.
- Gibbs PE, Dugaiczyk A
- Origin of structural domains of the serum-albumin gene family and a predicted structure of the gene for vitamin D-binding protein.
- Mol Biol Evol. 1987; 4: 364-79
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We have recently determined complete DNA sequences for the human albumin and alpha-fetoprotein [AFP] genes and thus have identified their detailed structures. Each is composed of three domains of four exons, three of which are internal and one of which is a domain-linking exon. Equivalent exons in each domain show sufficient sequence and structural similarity to be considered homologous; additional unique exons at each end of the gene show no similarity to the internal triplicated structures. Since earlier, conflicting evolutionary models were based on analysis of single gene structures, we derived from five genes a series of consensus sequences representing the three internal exons as well as the domain-linking exon. The five genes were human and rat albumin and human, mouse, and rat AFP genes. Structurally equivalent exons of the different domains are shown to have arisen from a single exon in a one-domain precursor. Exons that bridge the domains arose from an unequal crossover that fused two exons of the precursor. Our model suggests that part of the coding sequence of the one-domain precursor may have been derived from an intron, by way of loss of a splice site. The consensus sequences were used to propose an intron-exon structure for the related gene encoding the serum vitamin D-binding protein (DBP). DBP is truncated relative to albumin and AFP, and we submit that this results from deletion of two internal exons in the third domain of the gene rather than from premature termination of the coding sequence.
- Moro R, Villacampa MJ
- Short sequences of high homology between the primary structures of alpha-fetoprotein and albumin.
- Tumour Biol. 1986; 7: 115-21
- Display abstract
Several reports have shown a high percentage of homology between the primary structures of alpha-fetoprotein (AFP) and serum albumin (Alb). With the aid of a program which searches for all identical sequences, we compared the aminoacid sequence of AFP and Alb from several species. Two short pieces of very high homology were always present in all the AFPs and Albs studied, but in none of the other analyzed proteins. One is in Domain I (16 amino acids long) and the other in Domain III (17 residues long). The implications of this finding in relation to the function and evolution of AFP and Alb are discussed.
- Minghetti PP, Law SW, Dugaiczyk A
- The rate of molecular evolution of alpha-fetoprotein approaches that of pseudogenes.
- Mol Biol Evol. 1985; 2: 347-58
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We conducted the present study in an attempt to correlate function with the rate of molecular evolution for serum albumin and alpha-fetoprotein. We found a high rate of silent substitution (between 5 X 10(-9) and 7 X 10(-9)/site/year) for both the albumin and alpha-fetoprotein genes, perhaps the highest so far reported for an expressed nuclear gene. The rates of effective substitution and amino acid changes were also very high, but in contrast to silent substitutions, they are higher for alpha-fetoprotein than for albumin by approximately 70%. For alpha-fetoprotein, the rate of effective substitution (1.5 X 10(-9)/site/year) may be approaching that for nonfunctional pseudogenes (about 3 X 10(-9)/site/year). Evolutionary divergence was also estimated at the amino acid level. It was found that the rate of change of alpha-fetoprotein (55% amino acids replaced in 100 Myr) approaches that of the fastest-evolving fibrinopeptides (92% amino acids replaced in 100 Myr). This high rate may indicate that alpha-fetoprotein can tolerate a great deal of molecular variation without its function being impaired in the process. Albumin evolves at a slower rate (39% amino acids replaced in 100 Myr), although still faster than either hemoglobin (17% amino acids replaced in 100 Myr) or cytochrome c (5% amino acids replaced in 100 Myr). The slower evolutionary rate may indicate that albumin has more refined functional specifications and hence can tolerate fewer mutational changes. The latter conclusion remains, however, to be reconciled with the condition of inherited analbuminemia, where a virtually complete absence of albumin produces surprisingly few symptoms.
- Yang F, Luna VJ, McAnelly RD, Naberhaus KH, Cupples RL, Bowman BH
- Evolutionary and structural relationships among the group-specific component, albumin and alpha-fetoprotein.
- Nucleic Acids Res. 1985; 13: 8007-17
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The group-specific component (Gc) is a plasma protein that binds vitamin D. Recent characterization of human Gc cDNA demonstrated homology with serum albumin and alpha-fetoprotein. This study compares the sequences of the three proteins and demonstrates a strong evolutionary relationship. Albumin, alpha-fetoprotein and Gc evolved from an ancestral gene containing an intragenic triplication. Comparison of the amino acid sequences and patterns of double disulfide bonds suggests that the Gc gene may have diverged from an ancestral gene earlier in evolution than the genes encoding albumin and alpha-fetoprotein. Analysis of the amino acid and nucleotide sequences of the three internal domains of Gc revealed 19-23% amino acid sequence identity and the localization of three homology blocks with 40-44% nucleotide sequence identity. The deduced amino sequence of Gc furnished data for comparing its molecular configuration based on the predicted secondary structure with those predicted for human albumin and alpha-fetoprotein. Utilization of Gc cDNA has also led to the identification of its genomic DNA and detection of a human DNA polymorphism.
- Ghazal P, Clark AJ, Bishop JO
- Evolutionary amplification of a pseudogene.
- Proc Natl Acad Sci U S A. 1985; 82: 4182-5
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The family of mouse major urinary protein (MUP) genes has about 35 members, clustered together on chromosome 4. Most of the genes belong to two major subfamilies (group 1 and group 2) each with 12-15 members. Recently we showed that most of the group 1 and group 2 genes are arranged in pairs, each containing a group 1 and a group 2 gene in divergent transcriptional orientation, with 15 kilobases of DNA between the two cap sites. Here we present the nucleotide sequence of the first exon of six group 1 genes and four group 2 genes. The data confirm the close relationship of the genes within each group and the considerable divergence of the two groups from each other. The four group 2 genes all carry the same nonsense mutation in codon 7 of the sequence that specifies the mature protein. Thus, not only do these genes have a common ancestor, but also it seems that their amplification followed the mutation of the ancestor to a pseudogene. Taking into account the 3' flanking regions of the two genes, the overall size of each gene-pair is about 45 kilobases. The sequencing data supports our earlier suggestion that this 45 kilobase domain is the unit of Mup amplification.
- Sakai M
- [Structure and expression of the alpha-fetoprotein gene]
- Seikagaku. 1985; 57: 30-5
- Cooper R et al.
- Localization of the L1Md family of repeated sequences in the mouse albumin-alpha-fetoprotein gene complex.
- Nucleic Acids Res. 1984; 12: 6575-86
- Display abstract
Studies on the beta-globin gene complex in the mouse have demonstrated the existence of repeated DNA sequences interspersed throughout the intergenic regions (1,2). These sequences are members of families of middle repetitive sequences and have been mapped to specific intergenic sites in the 60 kbp beta-globin complex. In this study we present evidence that members of this middle repetitive family of DNA sequences, the L1Md family, are interspersed throughout the mouse albumin and alpha-fetoprotein gene complex. Unlike those of the beta-globin complex, all of which are found in the intergenic regions, these sequences are localized within intron 12 of the albumin gene and intron 3 of the AFP gene as well as twice in the 13.5 kbp intergenic region that links the albumin gene to the AFP gene.
- Young PR, Litwin S
- Determination of the likelihood of repetitive sequences in the alpha-fetoprotein gene.
- J Mol Biol. 1984; 173: 174-6
- Latchman DS, Brzeski H, Lovell-Badge R, Evans MJ
- Expression of the alpha-fetoprotein gene in pluripotent and committed cells.
- Biochim Biophys Acta. 1984; 783: 130-6
- Display abstract
We have studied the structure and expression of the alpha-fetoprotein gene in various cell types which differ in their capacity to synthesize alpha-fetoprotein. In all cells and tissues examined the levels of alpha-fetoprotein RNA found in the nucleus and cytoplasm were consistent with the hypothesis that alpha-fetoprotein expression is transcriptionally regulated. The alpha-fetoprotein gene was insensitive to deoxyribonuclease I in both undifferentiated embryonal carcinoma cells and in differentiated tissues which do not express alpha-fetoprotein, whereas in endoderm cells derived from the embryonal carcinoma cells and in alpha-fetoprotein-producing tissues the gene was sensitive to deoxyribonuclease I.
- Scott RW, Vogt TF, Croke ME, Tilghman SM
- Tissue-specific activation of a cloned alpha-fetoprotein gene during differentiation of a transfected embryonal carcinoma cell line.
- Nature. 1984; 310: 562-7
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To identify cis-acting DNA elements involved in the activation of the alpha-fetoprotein gene during differentiation, modified copies of the gene were introduced into murine F9 embryonal carcinoma cells. The differentiation of the transformants to either parietal or visceral endoderm was accompanied by induction of the exogenous template in a manner qualitatively, but not quantitatively, identical to that of the endogenous alpha-fetoprotein gene.
- Hwu HR, Papaconstantinou J, Holoubek V
- Location of DNA sequences complementary to small nuclear repeat RNA (fr 3-RNA) in relation to DNA sequences coding for albumin and alpha-fetoprotein in rat liver cells.
- Biochim Biophys Acta. 1984; 782: 164-9
- Display abstract
Rat liver nuclei contain a 29-nucleotides-long RNA (fr 3-RNA) which is transcribed from middle repetitive DNA sequences. By Southern analysis of restriction fragments of rat albumin and alpha-fetoprotein genomic clones, DNA sequences complementary to this RNA were detected on a 4.6 kbp Eco RI fragment located 600 bp downstream from the termination exon of the albumin gene and on a 2 kbp Eco RI-HindIII fragment located 10 kbp downstream from the restriction fragment containing the alpha-fetoprotein site. No sequence complementary to this RNA was found either in the introns of exons of both genes or in the regions extending 7 kbp upstream from the first albumin exon and 10 kbp upstream of the first alpha-fetoprotein exon. We concluded that sequences complementary to fr 3-RNA are present at the 3'-end flanking regions of the rat albumin and alpha-fetoprotein gene complexes.
- Harper ME, Dugaiczyk A
- Linkage of the evolutionarily-related serum albumin and alpha-fetoprotein genes within q11-22 of human chromosome 4.
- Am J Hum Genet. 1983; 35: 565-72
- Display abstract
Albumin and alpha-fetoprotein are structurally related serum proteins, having a similar gene structure and, conceivably, a common evolutionary origin. To test their relative arrangement in the human genome, the serum albumin and alpha-fetoprotein genes were mapped by in situ hybridization of cloned human albumin or alpha-fetoprotein cDNA to human mitotic chromosome preparations. Analysis of cells hybridized with the serum albumin probe showed that 39% of cells exhibited grains on the proximal portion of the long arm of chromosome 4 (bands q11-22), with these grains comprising 30% of all labeled sites throughout these mitoses. Similarly, in cells hybridized with the alpha-fetoprotein probe, 39% of cells were observed to contain silver grains on 4q11-22, these grains constituting 20% of all labeled sites in these cells. These results demonstrate chromosomal localization and linkage of the serum albumin and alpha-fetoprotein genes within bands q11-22 of the long arm of human chromosome 4.
- Tamaoki T
- [Structure and expression of alpha-fetoprotein gene--current progress in research]
- Gan To Kagaku Ryoho. 1983; 10: 623-30
- Display abstract
alpha-Fetoprotein (AFP) is of great biological and medical interest because its concentration in the serum often increases drastically in association with the development of hepatomas and germ cell tumors. Thus, studies of mechanisms of regulation of AFP synthesis may contribute to our understanding of normal and neoplastic growth processes. This article will review recent advances in the study of the structure, expression and regulation of the AFP gene in normal and malignant cells.
- Morinaga T, Sakai M, Wegmann TG, Tamaoki T
- Primary structures of human alpha-fetoprotein and its mRNA.
- Proc Natl Acad Sci U S A. 1983; 80: 4604-8
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DNA complementary to human alpha-fetoprotein (AFP)mRNA was cloned in the plasmid pBR322. Analysis of three overlapping cDNA clones revealed most of the nucleotide sequence of AFP mRNA, and the remaining nucleotides at the 5' end of the mRNA were elucidated from a cloned genomic DNA fragment. The amino acid sequence was deduced from the nucleotide sequence, which revealed 19 amino acids in the signal sequence and 590 amino acids in mature AFP. There are 15 regularly spaced disulfide bridges, which generate a folding structure having three repeating domains. There is one potential N-glycosylation site, Asn-Phe-Thr, in the amino acid sequence. In comparison with mouse AFP, 66% of the amino acid sequence was conserved, with the highest identity (72%) in domain 3, followed by domain 2 (67%) and domain 1 (59%). In comparison with human albumin, a 39% conservation of primary structure was found. Again, the similarity was the highest in domain 3 and the lowest in domain 1. Human AFP and human albumin are similar in overall structure, but certain parts of the molecules differ significantly in their predicted secondary structure.
- Cook JR, Chiu JF
- Effect of 5-azacytidine on rat liver alpha-fetoprotein gene expression.
- Biochem Biophys Res Commun. 1983; 116: 939-44
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Neonatal rats given 5-azacytidine intraperitoneally (30 micrograms/animal/day) on days 1-5 postpartum had 55% lower serum alpha-fetoprotein levels on day 6 compared to saline injected controls. On day 14, alpha-fetoprotein levels were 4-fold lower in 5-azacytidine treated animals. Cytosol alpha-fetoprotein was proportionately reduced. There were no significant changes in liver to body weight ratio, total serum protein, and both serum and cytosol albumin levels. The molecular basis for decreased serum alpha-fetoprotein levels was found to be a reduced concentration of alpha-fetoprotein mRNA in the livers of 5-azacytidine injected animals. These results are discussed with respect to the effects of 5-azacytidine on DNA methylation and cell differentiation.
- Tilghman SM, Belayew A
- Transcriptional control of the murine albumin/alpha-fetoprotein locus during development.
- Proc Natl Acad Sci U S A. 1982; 79: 5254-7
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The ontogeny of expression of the alpha-fetoprotein (AFP) and albumin genes was examined in livers from late prenatal to 1-month-postpartum C3H/He mice. A parallel accumulation of both AFP and albumin mRNAs before birth, followed by a selective nonreciprocal decrease in AFP mRNA after birth, was observed. The decrease in AFP mRNA was the result of a decrease in transcription of the AFP gene, as measured by an in vitro nuclear transcription assay. We suggest a model for hepatic expression of the AFP and albumin gene cluster in which transcription of the two genes is activated simultaneously during differentiation and each gene is thereafter modulated independently in committed cells.
- Young PR, Scott RW, Hamer DH, Tilghman SM
- Construction and expression in vivo of an internally deleted mouse alpha-fetoprotein gene: presence of a transcribed Alu-like repeat within the first intervening sequence.
- Nucleic Acids Res. 1982; 10: 3099-116
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An alpha-fetoprotein (AFP) 'minigene' was constructed by joining the first two exons along with 0.9 kilobases of 5' flanking sequence of the mouse AFP gene to its last exon and 0.4 kilobases of 3' flanking sequence. This 'minigene' was tested for activity by inserting it into an SV40 vector and infecting African green monkey kidney cells. Correct initiation, termination, polyadenylation and splicing were observed. Furthermore a 220 nucleotide transcript was detected and mapped to a mouse Alu-like or B1 repeat on the opposite strand to that encoding the AFP gene in the first intervening sequence.
- Andrews GK, Dziadek M, Tamaoki T
- Expression and methylation of the mouse alpha-fetoprotein gene in embryonic, adult, and neoplastic tissues.
- J Biol Chem. 1982; 257: 5148-53
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Expression of the mouse alpha-fetoprotein gene in embryonic, adult, and neoplastic tissues was assessed by RNA dot hybridization using 32P-labeled alpha-fetoprotein cDNA as probe, alpha-fetoprotein mRNA was present in high levels in total RNA from yolk sac endoderm, fetal liver, and an alpha-fetoprotein-producing hepatoma. In contrast, this mRNA was greatly depleted in total RNA from yolk sac mesoderm and essentially absent in brain, adult liver, and a non-alpha-fetoprotein-producing hepatoma. These results indicated that alpha-fetoprotein gene expression was controlled primarily at the transcriptional level. The presence of the modified base, 5-methylcytosine, in the alpha-fetoprotein gene was studied by comparing hybridization patterns obtained by Southern blot analysis of DNA cleaved with the restriction endonuclease isoschizomers Msp I and Hpa II. The gross sequence organization and reiteration frequency of the alpha-fetoprotein gene were invariant among the DNA samples, whereas, in each case, there was a positive correlation between hypomethylation of six CCGG (Hpa II) sites in the alpha-fetoprotein gene and expression of this gene. These Hpa II sites were distributed throughout a large portion of the alp]a-fetoprotein gene. Patterns of cytosine methylation in this gene were established before day 15 of gestation in yolk sac endoderm and mesoderm.
- Beattie WG, Dugaiczyk A
- Structure and evolution of human alpha-fetoprotein deduced from partial sequence of cloned cDNA.
- Gene. 1982; 20: 415-22
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The nucleotide sequence of a recombinant DNA clone, containing a partial mRNA sequence for human alpha-fetoprotein (AFP) in the plasmid vector pBR322, has been determined. Two regions of the cloned nucleotide sequence were found to agree with published amino acid sequences of two cyanogen bromide peptides derived from human AFP. Examination of the amino acid sequence, deduced from the cloned portion of the mRNA coding region, reveals extensive homology with the third domain of the human serum albumin molecule. A total of 44% (56/128) amino acids and 54% (207/384) nucleotides are identical in the two structures. The landmark cysteine residues are found in the same positions in both polypeptide chains, presumably forming the same disulfide bridges in AFP as those found in the albumin. The sequence homology reinforces the evidence that human AFP and albumin constitute a gene family, in analogy to the same family found in rodents. A comparison of the human and rodent sequence data suggests that the rate of molecular evolution has been faster for AFP than for albumin.
- Sargent TD, Jagodzinski LL, Yang M, Bonner J
- Fine structure and evolution of the rat serum albumin gene.
- Mol Cell Biol. 1981; 1: 871-83
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The exons, their boundaries, and approximately half of the intronic deoxyribonucleic acid of the rat serum albumin gene were sequenced. In addition to the 14 exons identified earlier by R-loop analysis, a small exon was detected between the "leader" exon (Z) and exon B. The leader exon encoded the 5'-untranslated portion of albumin messenger ribonucleic acid and the "pre-pro" oligopeptide present on the nascent protein. The sites of initiation and termination of transcription were tentatively identified by comparison of the 5' and 3' gene-flanking sequences with those of other eucaryotic genes. All 28 intron/exon junctions conformed to the "GT-AG rule" (Breathnach et al., Proc. Natl. Acad. Sci. 75:4853-4857, 1978). The three homologous domains of albumin were encoded by three subgenes that consisted of four exons each and evolved by intragenic duplication of a common ancestor. The second and forth exons of each subgene appeared to be the result of an even earlier duplication event. We propose a model for the evolution of this gene that accounts for the observed patterns of exon size and homology.
- Law SW, Dugaiczyk A
- Homology between the primary structure of alpha-fetoprotein, deduced from a complete cDNA sequence, and serum albumin.
- Nature. 1981; 291: 201-5
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The entire DNA complementary to murine alpha-fetoprotein mRNA has been cloned in the plasmid vector pBR322 and its complete nucleotide sequence determined. The deduced amino acid sequence identifies a hydrophobic prepeptide of 19 amino acids and the complete primary structure of alpha-fetoprotein. Its structure reveals extensive homology to serum albumin and suggests that there are 15 disulphide bridges in the alpha-fetoprotein molecule, all at the same positions as those found in albumin. The AFP molecule can be organized into a three-domain structure almost identical to that of serum albumin, suggesting a common ancestral origin of the two proteins.
- Gorin MB, Cooper DL, Eiferman F, van de Rijn P, Tilghman SM
- The evolution of alpha-fetoprotein and albumin. I. A comparison of the primary amino acid sequences of mammalian alpha-fetoprotein and albumin.
- J Biol Chem. 1981; 256: 1954-9
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The amino acid sequence of mouse alpha-fetoprotein has been deduced from the nucleotide sequence of its mRNA and three chimeric plasmids containing overlapping segments of its cDNA. A comparison of the amino acid sequence with that of either human and bovine albumin reveals in each case a 32% conservation of primary sequence. In addition, using the regularly spaced positions of cystine bridges, a 2-dimensional structure was generated, which revealed the presence of 3 closely related domains within alpha-fetoprotein. The structures of these domains are identical with the triplicated domains previously observed in several mammalian albumins. These homologies lend strong circumstantial evidence to the proposal that these two proteins arose in evolution as the consequence of a duplication in a common tripartite ancestral gene.
- Kioussis D, Eiferman F, van de Rijn P, Gorin MB, Ingram RS, Tilghman SM
- The evolution of alpha-fetoprotein and albumin. II. The structures of the alpha-fetoprotein and albumin genes in the mouse.
- J Biol Chem. 1981; 256: 1960-7
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The murine alpha-fetoprotein (AFP) and albumin genes have been cloned from genomic libraries derived from Balb/c DNA. By restriction endonuclease mapping and electron microscopy, we have shown that both genes are organized similarly into 15 coding segments interrupted by 14 intervening sequences. The sizes of the corresponding coding segments in each gene are identical, lending support to the hypothesis that the two genes, were derived from a common ancestral gene. However, no nucleotide homology between coding segments was observed. Both the sizes and the nucleotide sequence of flanking and intervening sequences have diverged significantly as well. Two regions of the AFP gene, 925 base pairs in the 5' flanking DNA and 180 base pairs in the third intervening sequence, hybridized to the same region of DNA in the third intervening sequence of albumin. The 180-base pair homologies within each gene are present in opposite orientation relative to the direction of transcription, and are associated with reiterated DNA. Thus, it is unlikely that they represent true sequence conservation. An examination of the sizes of the coding segments in each gene reveals a thrice repeated domain, consisting of 4 coding segments. We propose that these correspond to the three domains observed in several mammalian albumins, and in murine AFP.
- Zizkovsky V, Strop P, Lukesova S, Korcakova J, Dvorak P
- Similarity of hydrophobic properties of alpha-fetoprotein and albumin.
- Oncodev Biol Med. 1981; 2: 323-30
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Human alpha-fetoprotein (AFP) and serum albumin (HSA) were studied by hydrophobic interaction chromatography. A close resemblance was observed both in the native state and after various perturbations (pH, salt and alcohol) indicating a significant similarity in their molecular structures. Both proteins displayed similar hydrophobic properties which apparently were different from those of other globular proteins. In agreement with the domain structure proposed by Brown (1976), our results indicated that surface nonpolar side chains of both the native HSA and AFP produced large hydrophobic areas located solely in crevices.
- Jagodzinski LL, Sargent TD, Yang M, Glackin C, Bonner J
- Sequence homology between RNAs encoding rat alpha-fetoprotein and rat serum albumin.
- Proc Natl Acad Sci U S A. 1981; 78: 3521-5
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We have determined the sequences of the recombinant DNA inserts of three bacterial plasmid cDNA clones containing most of the rat alpha a-fetoprotein mRNA. The resultant nucleotide sequence of alpha-fetoprotein was exhaustively compared to the nucleotide sequence of the mRNA encoding rat serum albumin. These two mRNAs have extensive homology (50%) throughout and the same intron locations. The amino acid sequence of rat alpha-fetoprotein has been deduced from the nucleotide sequence, and its comparison to rat serum albumin's amino acid sequence reveals a 34% homology. The regularly spaced positions of the cysteines found in serum albumin are conserved in rat alpha-fetoprotein, indicating that these two proteins may have a similar secondary folding structure. These homologies indicate that alpha-fetoprotein and serum albumin were derived by duplication of a common ancestral gene and constitute a gene family.
- Ohno S
- Original domain for the serum albumin family arose from repeated sequences.
- Proc Natl Acad Sci U S A. 1981; 78: 7657-61
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The characteristic three-domain structure has been conserved throughout mammalian evolution by serum albumin and its fetal counterpart, alpha-fetoprotein. Thus, one still detects 35.2% amino acid sequence homology between bovine serum albumin and murine alpha-fetoprotein. Yet, natural selection cannot be invoked as the major factor responsible for the observed conservation of these sequences, for the simple reason of their dispensability. Inherited analbuminemia is apparently a harmless trait in man and the rat. The conservation appears inherent in their repetitious origin. Each protein is made of triplicate copies of the ancestral domain. Furthermore, analysis of the published sequence data suggests that the original coding sequence for the ancestral domain arose as repeats of the 18-base-long primordial building block sequence TTC-ACA-GAG-GAG-CAG-CTG specifying Phe-Thr-Glu-Glu-Gln-Leu and its shorter subsidiary TTC-ATG-GAG-GAG specifying Phe-Met-Glu-Glu. Consequently, the homology between bovine serum albumin and alpha-fetoprotein is mostly confined to small segments still specified by recognizable descendants of these building block sequences. The point to be made here is that evolutionary conservation of coding sequences can be an inherent property; natural selection need not be invoked.
- Ingram RS, Scott RW, Tilghman SM
- alpha-Fetoprotein and albumin genes are in tandem in the mouse genome.
- Proc Natl Acad Sci U S A. 1981; 78: 4694-8
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The urine alpha-fetoprotein (AFP) and serum albumin genes most probably arose in evolution as the consequence of a duplication of a common ancestral gene. They have both been previously mapped to chromosome 5 in the mouse. We now have evidence that these genes are closely linked. By using a unique copy DNA probe derived from previously cloned AFP 5' flanking DNA, a recombinant DNA phage has been isolated, from a bacteriophage DNA library, that contains sequences flanking the 5' end of the AFP gene and the 3' end of the albumin gene. Restriction endonuclease mapping and DNA sequence determination of the recombinant phage and comparison to total genomic DNA confirmed that the genes are in tandem, 13.5 kilobase pairs apart, with the albumin gene to the 5' side of the AFP gene. Thus, they are transcribed from the same strand of DNA.
- Choi N, Higashi T
- Studies on the activity of alpha-fetoprotein gene.
- Chem Pharm Bull (Tokyo). 1981; 29: 3311-9
- Yamada Y et al.
- The collagen gene: evidence for its evolutinary assembly by amplification of a DNA segment containing an exon of 54 bp.
- Cell. 1980; 22: 887-92
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We have determined the size and sequence of 8 exons in the gene that specifies chick type 1 alpha 2 collagen. These 8 exons represent three different segments of the gene, but all encode information for the helical portion of the protein. Seven exons have a length of 54 bp, and the 8th has a size of 99 bp. The sequences within these exons vary except for th glycine codons, which occur every third triplet. Each exon begins with a glycine codon and ends with a triplet that precedes a glycine codon. The size and the sequences of the introns do not show any homology except at their ends. Of 7 introns examined the first six bases at the 5' end of 5 of these are identical. The sequences at the 3' end of the introns also show homologies. Our results imply that the ancestral gene for collagen arose by multiple duplications of a single genetic unit containing a 54 bp condig segment. The sequences within these exons drifted by successive point mutations and in some cases by additions or deletions of 9 bp or multiples of 9 bp.
- Weigand K
- [Synthesis, distribution and importance of serum albumin]
- Klin Anasthesiol Intensivther. 1980; 21: 52-64
- Liao WS, Hamilton RW, Taylor JM
- Amino acid sequence homology between rat alpha-fetoprotein and albumin at the COOH-terminal regions.
- J Biol Chem. 1980; 255: 8046-9
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The nucleotide sequence of the 3'-terminal untranslated region and a portion of the coding region of rat alpha-fetoprotein mRNA has been determined from a cloned double-stranded cDNA. the amino acid sequence of the COOH-terminal portion of alpha-fetoprotein was inferred from the nucleotide sequence and compared to the amino acid sequence of the corresponding portion of rat, bovine, and human albumin. A striking homology in amino acid sequence between alpha-fetoprotein and albumin was observed. These results confirm earlier suggestions that the two proteins are closely related in structure and probably arose from a common ancestral gene.
- Gorin MB, Tilghman SM
- Structure of the alpha-fetoprotein gene in the mouse.
- Proc Natl Acad Sci U S A. 1980; 77: 1351-5
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The mouse alpha-fetoprotein mRNA is the product of a single-copy gene whose mRNA coding sequences are represented discontinuously in the genome. Several EcoRI genomic fragments which contain portions of the alpha-fetoprotein gene have been cloned using the EK2 vector lambda gt WES . lambda B. In addition, a mouse genomic library has been screened to obtain a 15.75-kilobase segment of DNA that includes more than 85% of the alpha-fetoprotein coding sequence. Analyses by restriction endonuclease mapping and electron microscopy showed that the mRNA sequence is interrupted by at least 11 intervening sequences which occupy 90% of the cloned DNA.
- Franglen G
- The structure of human plasma albumin.
- Clin Sci. 1970; 39: 1-1
- Franglen G
- The role of plasma albumin and its relation to its structure.
- Proc R Soc Med. 1967; 60: 1072-4
