NORMAL GENOMIC

• Bergemann AD, Cole F, Hirschhorn K
• The etiology of Wolf-Hirschhorn syndrome.
• Trends Genet. 2005; 21: 188-95
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• Wolf-Hirschhorn syndrome (WHS) is defined by a collection of corecharacteristics, which include mental retardation, epilepsy, growth delayand cranio-facial dysgenesis. The disorder is caused by sub-telomericdeletions in the short arm of chromosome 4. The severity of the corecharacteristics is highly variable, and additional problems, includingmidline fusion defects, occur at lower frequency. Only one gene, WHSC1, isdeleted in every case. However, recent evidence, from patient studies andmouse models, indicates that deletion of WHSC1 alone is insufficient forfull-blown WHS. Instead a model is emerging in which deletion of WHSC1 isessential for pathogenesis, but deletion of linked genes contributes toboth the severity of the core characteristics and the presence of theadditional syndromic problems. In this article, we outline the progressbeing made in patient studies and in the development of mouse models, andrelate the implications of this work for a broad group of sub-telomericdeletion syndromes.

• Yonetani N, Ueda C, Akasaka T, Nishikori M, Uchiyama T, Ohno H
• Heterogeneous breakpoints on the immunoglobulin genes are involved infusion with the 5' region of BCL2 in B-cell tumors.
• Jpn J Cancer Res. 2001; 92: 933-40
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• The 5' flanking region of the BCL2 gene (5'-BCL2) is a breakpoint clusterof rearrangements with immunoglobulin genes (IGs). In contrast tot(14;18)(q32;q21) affecting the 3' region of BCL2, 5'-BCL2 can fuse to notonly the heavy chain gene (IGH), but also two light chain gene (IGL) loci.We report here cloning and sequencing of a total of eleven 5'-BCL2 / IGsjunctional areas of B-cell tumors, which were amplified by long-distancepolymerase chain reaction-based assays. The breakpoints on 5'-BCL2 weredistributed from 378 to 2312 bp upstream of the translational initiationsite and, reflecting the alteration of regulatory sequences of BCL2,5'-BCL2 / IGs-positive cells showed markedly higher levels of BCL2expression than those of t(14;18)-positive cells. In contrast, thebreakpoints on the IGs were variable. Two 5'-BCL2 / IGH and two 5'-BCL2 /IGLkappa junctions occurred 5' of the joining (J) segments, suggestingoperation of an erroneous variable (V) / diversity (D) / J and V / Jrearrangement mechanism. However, two other 5'-BCL2 / IGH junctionsaffected switch regions, and the kappa-deleting element, which is located24 kb downstream of the constant region of IGLkappa, followed the 5'-BCL2in another case. One 5'-BCL2 / IGLkappa and two 5'-BCL2 / IGLlambdajunctions involved intronic regions where the normal recombination processdoes not occur. In the remaining one case, the 5'-BCL2 fused 3' of aVlambda gene that was upstream of another Vlambda / Jlambda complexcarrying a non-producing configuration, indicating that the receptorediting mechanism was likely involved in this rearrangement. Our studyrevealed heterogeneous anatomy of the 5'-BCL2 / IGs fusion gene leading totranscriptional activation of BCL2, and suggested that the mechanismsunderlying the formation of this particular oncogene / IGs recombinationare not identical to those of t(14;18).

• Avet-Loiseau H et al.
• High incidence of cryptic translocations involving the Ig heavy chain genein multiple myeloma, as shown by fluorescence in situ hybridization.
• Genes Chromosomes Cancer. 1999; 24: 9-15
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• Cytogenetic studies have shown rearrangements of the Ig heavy chain (IGH)gene at 14q32 in 10-60% of patients with multiple myeloma (MM) or primaryplasma cell leukemia (PCL). Analysis of MM patients and human myeloma celllines (HMCL) using interphase fluorescence in situ hybridization (FISH)and molecular techniques has shown IGH rearrangements in 75% of MM casesand in up to 100% of HMCL. A review of the literature revealed at least 18different partner chromosomal regions. To investigate whether some ofthese translocations were recurrent and possibly to identify new partnerregions, we developed a set of FISH probes to detect every IGHrecombination. We analyzed 28 MM and 4 primary PCL patients with abnormalkaryotypes and 12 HMCL. Whereas conventional cytogenetics detected a 14q32abnormality in only 15% of the patients, FISH detected it in 47% ofpatients and in 75% of HMCL. The partner chromosome was identified in 10of 15 patients with a 14q32 rearrangement. Interestingly, the same t(4;14)(p16;q32) was detected in five patients and three HMCL, i.e., 33% ofpatients and HMCL with an IGH rearrangement. New partner chromosomalregions have also been identified, i.e., 9p13, 12p11, 12p13, and Xq28,besides the previously reported 8q24, 11q13, 12q24, and 16q24rearrangements. The genes involved in these new translocations are notknown, except for 9p13, where PAX5 was shown to be the partner gene. Weconclude that: I) IGH recombinations are frequent but not constant in MM,2) these rearrangements often occur through cryptic translocations, and 3)the t(4;14)(p16;q32) is one of the most frequent translocations, but manyother chromosomal regions may be involved.

• Taki T et al.
• ABI-1, a human homolog to mouse Abl-interactor 1, fuses the MLL gene inacute myeloid leukemia with t(10;11)(p11.2;q23).
• Blood. 1998; 92: 1125-30
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• Recurrent translocation t(10;11) has been reported to be associated withacute myeloid leukemia (AML). Recently, two types of chimeric transcripts,MLL-AF10 in t(10;11)(p12;q23) and CALM-AF10 in t(10;11)(p13;q14), wereisolated. t(10;11) is strongly associated with complex translocations,including invins(10;11) and inv(11)t(10;11), because the direction oftranscription of AF10 is telomere to centromere. We analyzed a patient ofAML with t(10;11)(p11.2;q23) and identified ABI-1 on chromosome 10p11.2, ahuman homolog to mouse Abl-interactor 1 (Abi-1), fused with MLL. Whereasthe ABI-1 gene bears no homology with the partner genes of MLL previouslydescribed, the ABI-1 protein exhibits sequence similarity to protein ofhomeotic genes, contains several polyproline stretches, and includes a srchomology 3 (SH3) domain at the C-terminus that is required for binding toAbl proteins in mouse Abi-1 protein. Recently, e3B1, an eps8 SH3 bindingprotein 1, was also isolated as a human homolog to mouse Abi-1. Threetypes of transcripts of ABI-1 gene were expressed in normal peripheralblood. Although e3B1 was considered to be a full-length ABI-1, theMLL-ABI-1 fusion transcript in this patient was formed by an alternativelyspliced ABI-1. Others have shown that mouse Abi-1 suppresses v-ABLtransforming activity and that e3B1, full-length ABI-1, regulates cellgrowth. In-frame MLL-ABI-1 fusion transcripts combine the MLL AT-hookmotifs and DNA methyltransferase homology region with the homeodomainhomologous region, polyproline stretches, and SH3 domain of alternativelyspliced transcript of ABI-1. Our results suggest that the ABI-1 gene playsa role in leukemogenesis by translocating to MLL.

• Stec I et al.
• WHSC1, a 90 kb SET domain-containing gene, expressed in early developmentand homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhornsyndrome critical region and is fused to IgH in t(4;14) multiple myeloma.
• Hum Mol Genet. 1998; 7: 1071-82
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• Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated witha hemizygous deletion of the distal short arm of chromosome 4 (4p16.3).The smallest region of overlap between WHS patients, the WHS criticalregion, has been confined to 165 kb, of which the complete sequence isknown. We have identified and studied a 90 kb gene, designated as WHSC1 ,mapping to the 165 kb WHS critical region. This 25 exon gene is expressedubiquitously in early development and undergoes complex alternativesplicing and differential polyadenylation. It encodes a 136 kDa proteincontaining four domains present in other developmental proteins: a PWWPdomain, an HMG box, a SET domain also found in the Drosophila dysmorphygene ash -encoded protein, and a PHD-type zinc finger. It is expressedpreferentially in rapidly growing embryonic tissues, in a patterncorresponding to affected organs in WHS patients. The nature of theprotein motifs, the expression pattern and its mapping to the criticalregion led us to propose WHSC1 as a good candidate gene to be responsiblefor many of the phenotypic features of WHS. Finally, as a serendipitousfinding, of the t(4;14) (p16.3;q32.3) translocations recently described inmultiple myelomas, at least three breakpoints merge the IgH and WHSC1genes, potentially causing fusion proteins replacing WHSC1 exons 1-4 bythe IgH 5'-VDJ moiety.

• Fath I et al.
• Identification of two human homologues to Drosophila SOS (son ofsevenless) localized on two different chromosomes.
• Nucleic Acids Res. 1993; 21: 4398-4398

• Kerckaert JP, Deweindt C, Tilly H, Quief S, Lecocq G, Bastard C
• LAZ3, a novel zinc-finger encoding gene, is disrupted by recurringchromosome 3q27 translocations in human lymphomas.
• Nat Genet. 1993; 5: 66-70
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• We have shown previously that chromosomal translocations involvingchromosome 3q27 and immunoglobulin gene regions are the third most commonspecific translocations in non-Hodgkin's lymphoma (NHL). We now report theisolation of a gene that is disrupted in two cases by t(3;14) and t(3;4)translocations. The gene (LAZ3) encodes a 79 kDa protein containing sixzinc-finger motifs and sharing amino-terminal homology with severaltranscription factors including the Drosophila tramtrack and Broad-complexgenes, both of which are developmental transcription regulators. LAZ3 istranscribed as a 3.8 kb message predominantly in normal adult skeletalmuscle and in several NHL carrying 3q27 chromosomal defects. We suggestthat it may act as a transcription regulator and play an important role inlymphomagenesis.

• Mihaesco E, Gendron MC, Congy N, Frangione B
• Protein Rou. A human IgA hybrid.
• J Immunol. 1988; 140: 1236-8
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• Protein Rou is a human IgA2 myeloma protein that carries the isoallotypemarker n A2m(2). Partial amino acid sequence of its H chain (alpha) showsthat the hinge region and the CH2 domain are homologous to alpha 2-chainand the CH1 and the CH3 domains homologous to alpha 1. Moreover, the CH1domain contains the H-L disulfide bond identical to alpha 1. It isconcluded that Rou H chain is a hybrid molecule caused by a recombinationbetween alpha 1 and alpha 2 genes. The recombination event occurredbetween alpha 1-exon 1 and alpha 2-exon hinge and corresponds to position222-223 of the alpha-chain.