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• W2029965540 abstract "SummaryVelo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans. It occurs with an estimated frequency of 1 in 4,000 live births. Most cases occur sporadically, indicating that the deletion is recurrent in the population. More than 90% of patients with VCFS and a 22q11 deletion have a similar 3-Mb hemizygous deletion, suggesting that sequences at the breakpoints confer susceptibility to rearrangements. To define the region containing the chromosome breakpoints, we constructed an 8-kb–resolution physical map. We identified a low-copy repeat in the vicinity of both breakpoints. A set of genetic markers were integrated into the physical map to determine whether the deletions occur within the repeat. Haplotype analysis with genetic markers that flank the repeats showed that most patients with VCFS had deletion breakpoints in the repeat. Within the repeat is a 200-kb duplication of sequences, including a tandem repeat of genes/pseudogenes, surrounding the breakpoints. The genes in the repeat are GGT, BCRL, V7-rel, POM121-like, and GGT-rel. Physical mapping and genomic fingerprint analysis showed that the repeats are virtually identical in the 200-kb region, suggesting that the deletion is mediated by homologous recombination. Examination of two three-generation families showed that meiotic intrachromosomal recombination mediated the deletion. Velo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans. It occurs with an estimated frequency of 1 in 4,000 live births. Most cases occur sporadically, indicating that the deletion is recurrent in the population. More than 90% of patients with VCFS and a 22q11 deletion have a similar 3-Mb hemizygous deletion, suggesting that sequences at the breakpoints confer susceptibility to rearrangements. To define the region containing the chromosome breakpoints, we constructed an 8-kb–resolution physical map. We identified a low-copy repeat in the vicinity of both breakpoints. A set of genetic markers were integrated into the physical map to determine whether the deletions occur within the repeat. Haplotype analysis with genetic markers that flank the repeats showed that most patients with VCFS had deletion breakpoints in the repeat. Within the repeat is a 200-kb duplication of sequences, including a tandem repeat of genes/pseudogenes, surrounding the breakpoints. The genes in the repeat are GGT, BCRL, V7-rel, POM121-like, and GGT-rel. Physical mapping and genomic fingerprint analysis showed that the repeats are virtually identical in the 200-kb region, suggesting that the deletion is mediated by homologous recombination. Examination of two three-generation families showed that meiotic intrachromosomal recombination mediated the deletion. A number of congenital-anomaly disorders are associated with rearrangements of human chromosome 22q11. The most common is velo-cardio-facial syndrome (VCFS; MIM 192430), an autosomal dominant disorder characterized by craniofacial anomalies, heart defects, and learning disabilities (Shprintzen et al. Shprintzen et al., 1978Shprintzen RJ Goldberg RB Lewin ML Sidoti EJ Berkman MD Argamaso RV Young D A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome.Cleft Palate J. 1978; 15: 56-62PubMed Google Scholar). It is phenotypically related to DiGeorge syndrome (DGS; MIM 188400) (DiGeorge DiGeorge, 1965DiGeorge A A new concept of the cellular basis of immunity.J Pediatr. 1965; 67: 907Abstract Full Text PDF Google Scholar), a more severe disorder. DGS is characterized by hypocalcemia, aplasia, or hypoplasia of the thymus gland, as well as by the clinical findings of VCFS. Patients with VCFS and DGS have similar 22q11 deletions, suggesting that these disorders have the same etiology (Driscoll et al. Driscoll et al., 1992Driscoll DA Spinner NB Budarf ML McDonald-McGinn DM Zackai EH Goldberg RB Shprintzen RJ et al.Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome.Am J Med Genet. 1992; 44: 261-268Crossref PubMed Scopus (314) Google Scholar; Scambler et al. Scambler et al., 1992Scambler PJ Kelly D Lindsay E Williamson R Goldberg R Shprintzen R Wilson DI et al.Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus.Lancet. 1992; 339: 1138-1139Abstract PubMed Scopus (348) Google Scholar). The estimated occurrence of VCFS/DGS is 1 in 4,000 live births, making it the most common microdeletion disorder in humans (Burn and Goodship Burn and Goodship, 1996Burn J Goodship J Congenital heart disease.in: Rimoin DL Connor JM Pyeritz RE 3rd ed. Emery and Rimoin's principles and practice of medical genetics. Vol 1. Churchill Livingstone, New York1996: 767-828Google Scholar). Most cases occur sporadically in the population, indicating that the 22q11 region is prone to rearrangements. To define the deletions among patients, we constructed a YAC-contig–based physical map of a 5-Mb region on 22q11 (Collins et al. Collins et al., 1995Collins JE Cole CG Smink LJ Garret CL Leversha MA Soderlund CA Maslen GL et al.A high-density contig map of human chromosome 22.Nature. 1995; 377: 367-379PubMed Google Scholar; Morrow et al. Morrow et al., 1995Morrow B Goldberg R Carlson C Das Gupta R Sirotkin H Collins J Dunham I et al.Molecular definition of the 22q11 deletions in velo-cardio-facial syndrome.Am J Hum Genet. 1995; 56: 1391-1403PubMed Google Scholar). A total of 15 consecutive highly polymorphic genetic markers, which were part of the physical map, were used to genotype 151 patients with VCFS (Carlson et al. Carlson et al., 1997Carlson C Sirotkin H Pandita R Goldberg R McKie J Wadey R Patanjali SR et al.Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.Am J Hum Genet. 1997; 61: 620-629Abstract Full Text PDF PubMed Scopus (286) Google Scholar). We found that 83% of the patients had a detectable 22q11 deletion. Haplotype analysis revealed that 90% of the VCFS patients with a deletion had a similar 3-Mb deletion (Carlson et al. Carlson et al., 1997Carlson C Sirotkin H Pandita R Goldberg R McKie J Wadey R Patanjali SR et al.Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.Am J Hum Genet. 1997; 61: 620-629Abstract Full Text PDF PubMed Scopus (286) Google Scholar). The finding that most of the deletions were similar suggested that there might be sequences at the breakpoints that confer susceptibility to chromosome rearrangements. To determine the nature of the sequences at the proximal and distal 3-Mb breakpoints, we defined the interval containing them by constructing high-resolution physical maps in their vicinity. The maps had an average spacing of 8 kb between PCR-based markers. It was previously shown by FISH that low-copy–repeat families flanked the VCFS/DGS region on 22q11 (Halford et al. Halford et al., 1993Halford S Lindsay E Nayudu M Carey AH Baldini A Scambler PJ Low-copy-number repeat sequences flank the DiGeorge/velo-cardio-facial syndrome loci at 22q11.Hum Mol Genet. 1993; 2: 191-196Crossref PubMed Scopus (66) Google Scholar). By using a physical mapping approach, we identified low-copy–repetitive sequences spanning both breakpoint intervals and designated them “VCFS-REPs.” Haplotype analysis of a large number of patients with VCFS with genetic markers that flank the repeat showed that the breakpoints occur within the repeat. Both the proximal and distal VCFS-REPs have a complex arrangement that contains a 200-kb region, comprised of a tandem set of genes and pseudogenes, flanked on either side by inverted subrepeats. Fingerprint analysis of clones that map to a 200-kb interval within the proximal and distal VCFS-REPs indicated that the two regions are almost identical in composition, suggesting that homologous recombination between them could mediate the rearrangement. The cosmid clone 57D10 was isolated from the gridded LL22NC03 cosmid library (Roswell Park Cancer Institute [RPCI]; P. de Jong, personal communication) and used for FISH mapping. The DNA was purified on Qiagen midi-preparation columns (Qiagen). To generate a labeled probe, 1 μg of purified DNA (five slides) was subjected to nick translation with biotin-16 dUTP (GibcoBRL BioNick labeling system). The human repetitive sequences were blocked by prehybridization with 50 g of CoT-1 DNA (GibcoBRL). Metaphase chromosomes were prepared, and the probe was detected by incubating the slides with an amplification sandwich of fluorescein-labeled avidin, anti-avidin antibodies, and fluorescein-labeled avidin and then by staining with propidium iodide (Oncor). To construct the high-resolution physical map, high-density gridded membranes containing the 25X bacterial artifical chromosome (BAC) (170 kb average insert size), the 16X P1 artificial chromosome (PAC) (120 kb average insert size), and the 8X flow-sorted cosmid libraries (LL22NCO3, 40 kb average insert size) (RPCI; P. de Jong, personal communication) were screened with pools of 8–12 different 32P-radiolabeled PCR products from genomic DNA (Random Primed DNA Labeling Kit, Boehringer Mannheim). The positive clones were isolated, and DNA was prepared (Qiagen). The marker content of individual clones was verified by PCR analysis using 50 ng of template DNA under standard amplification conditions (Perkin-Elmer). The ends of the newly identified clones were sequenced by means of ABI377 automated sequencing machines. Each of the sequences was analyzed in Genbank by use of Blast Search, to eliminate highly repetitive elements. Primers for PCR were generated from the sequence (PRIMER Program) and were used as probes to rescreen the libraries. The genomic walking cycles were repeated until the gaps in the physical map were closed. Genomic DNA was prepared from 5 ml of peripheral blood obtained from patients BM103 and BM413 and their family members, with their informed consent (Human Genetics Program, Albert Einstein College of Medicine), by use of the Puregene protocol (Gentra) as described elsewhere (Carlson et al. Carlson et al., 1997Carlson C Sirotkin H Pandita R Goldberg R McKie J Wadey R Patanjali SR et al.Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.Am J Hum Genet. 1997; 61: 620-629Abstract Full Text PDF PubMed Scopus (286) Google Scholar). The blood samples from each of the individuals in this study were collected through a program approved by the internal review board. A maximum of 15 highly polymorphic genetic markers, from D22S420 to D22S257, were used for genotyping each individual, as described elsewhere (Carlson et al. Carlson et al., 1997Carlson C Sirotkin H Pandita R Goldberg R McKie J Wadey R Patanjali SR et al.Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.Am J Hum Genet. 1997; 61: 620-629Abstract Full Text PDF PubMed Scopus (286) Google Scholar). To define the interval containing the proximal and distal breakpoints leading to the common 3-Mb deletion in patients with VCFS, we constructed a high-resolution physical map. To initiate map assembly, sequence-tagged–site markers (Green and Olson Green and Olson, 1990Green ED Olson MV Chromosomal region of the cystic fibrosis gene in yeast artificial chromosomes: a model for human genome mapping.Science. 1990; 250: 94-98Crossref PubMed Scopus (226) Google Scholar), which were integrated into the YAC-contig–based physical map of 22q11 (Collins et al. Collins et al., 1995Collins JE Cole CG Smink LJ Garret CL Leversha MA Soderlund CA Maslen GL et al.A high-density contig map of human chromosome 22.Nature. 1995; 377: 367-379PubMed Google Scholar; Morrow et al. Morrow et al., 1995Morrow B Goldberg R Carlson C Das Gupta R Sirotkin H Collins J Dunham I et al.Molecular definition of the 22q11 deletions in velo-cardio-facial syndrome.Am J Hum Genet. 1995; 56: 1391-1403PubMed Google Scholar), were used as probes to screen bacterial libraries containing human genomic DNA inserts (Iaonnou et al. Iaonnou et al., 1994Iaonnou PA Amemiya CT Garnes J Kroisel PM Shizuya H Chen C Batzer MA et al.A new bacteriophage P1-derived vector for the propagation of large human DNA fragments.Nat Genet. 1994; 6: 84-89Crossref PubMed Scopus (754) Google Scholar). Surprisingly, clones that mapped to the proximal breakpoint interval were positive for markers known to map to the distal breakpoint interval and vice versa. These initial results suggested that both regions shared a high degree of sequence homology or identity. To directly examine whether sequences at the proximal and distal breakpoint intervals were repeated, we performed FISH mapping with a cosmid from the distal breakpoint interval, termed “57D10” (fig. 1). The assignment of this cosmid to the distal breakpoint interval will be clarified later. The distance between the proximal and distal breakpoint interval is 3 Mb, which is below the resolution of metaphase FISH (fig. 1A). To separate the proximal from the distal region, we performed FISH on cells from a t(2;22) balanced translocation found in a patient with VCFS/DGS, called “ADU” (Augusseau et al. Augusseau et al., 1986Augusseau S Jouk S Jalbert P Prieur M DiGeorge syndrome and 22q11 rearrangements.Hum Genet. 1986; 74: 206Crossref PubMed Scopus (90) Google Scholar). The ADU breakpoint has been cloned and sequenced (Budarf et al. Budarf et al., 1995Budarf ML Collins J Gong W Roe B Wang Z Bailey LC Sellinger B et al.Cloning a balanced translocation associated with DiGeorge syndrome and identification of a disrupted candidate gene.Nat Genet. 1995; 10: 269-278Crossref PubMed Scopus (131) Google Scholar) and has been integrated into the physical map (Carlson et al. Carlson et al., 1997Carlson C Sirotkin H Pandita R Goldberg R McKie J Wadey R Patanjali SR et al.Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.Am J Hum Genet. 1997; 61: 620-629Abstract Full Text PDF PubMed Scopus (286) Google Scholar). Patient ADU has a translocation breakpoint 160 kb distal to the common VCFS proximal breakpoint, placing the proximal and distal breakpoints on two distinct derivative chromosomes. If the sequences in 57D10 are duplicated in 22q11, three sets of signals would be observed, one on the normal copy of chromosome 22, one on the der(2) chromosome, and one on the der(22) chromosome. Three sets of signals were indeed detected on the chromosomes of patient ADU (fig. 1B), supporting the hypothesis that sequences in the vicinity of the breakpoints were duplicated. We designated the low-copy repeats at the proximal and distal breakpoint intervals as VCFS-REPs. A physical map of the breakpoint sites was constructed by screening PAC and BAC libraries, establishing their marker content and chromosome walking to fill gaps. We found that none of the bacterial clones were able to bridge the region containing the repeated markers. This indicated that the sizes of the proximal and distal repeats were greater than the size of the largest anchored clone. To unambiguously assign clones to either the proximal or distal VCFS-REP, we developed a unique anchored marker from within the repeated sequences. One marker was generated from the gamma-glutamyl transpeptidase gene (GGT; Courtay et al. Courtay et al., 1994Courtay C Heisterkamp N Siest G Groffen J Expression of multiple gamma-glutamyltransferase genes in man.Biochem J. 1994; 297: 503-508Crossref PubMed Scopus (46) Google Scholar), which maps to both the proximal and distal breakpoint intervals (fig. 2). Single-nucleotide polymorphisms in the GGT genes (Courtay et al. Courtay et al., 1994Courtay C Heisterkamp N Siest G Groffen J Expression of multiple gamma-glutamyltransferase genes in man.Biochem J. 1994; 297: 503-508Crossref PubMed Scopus (46) Google Scholar; Collins et al. Collins et al., 1997Collins JE Mungall AJ Badcock KL Fay JM Dunham I The organization of the gamma-glutamyl transferase genes and other low copy repeats in human chromosome 22q11.Genome Res. 1997; 7: 522-531PubMed Google Scholar) were used to distinguish the proximal from the distal copy (fig. 3). Restriction-fragment analysis of a 390-bp PCR product from a segment of the GGT genes (GGT-AMP) showed that the GGT genes in the proximal and distal copies of the VCFS-REPs belonged to the class termed “GGT.2” (Collins et al. Collins et al., 1997Collins JE Mungall AJ Badcock KL Fay JM Dunham I The organization of the gamma-glutamyl transferase genes and other low copy repeats in human chromosome 22q11.Genome Res. 1997; 7: 522-531PubMed Google Scholar). However, there were three distinct genes reported to belong to the GGT.2 class—genes 3, 11, and 13. To determine which of the GGT.2 genes mapped to the VCFS breakpoints, we digested the GGT.2-AMP PCR products with Bsp1286E, and two distinct restriction patterns were identified. These restriction patterns can be used to distinguish gene 3 from gene 11 or 13 (fig. 3A). To further distinguish genes 11 and 13, the GGT.2-AMP PCR products were sequenced (fig. 3B). By using this approach, we determined that clones anchored to the distal VCFS-REP contain GGT.2–gene 3, and those that anchor to the proximal VCFS-REP contain GGT.2–gene 13. This strategy allowed us to construct a complete sequence-ready physical map of the breakpoint regions. This map, estimated to cover 720 kb in the proximal region and 920 kb in the distal region, contained 103 and 92 markers, respectively, and provides an average resolution of 8.5 kb.Figure 3Analysis of the GGT.2 genes. A, GGT.2 clones were mapped to either the proximal or distal VCFS-REP by generation of the GGT-AMP PCR products, followed by restriction digestion with Bsp1286E endonuclease. Clones that mapped to the distal VCFS-REP contained GGT.2–gene 3 and produced characteristic restriction fragments. Clones that mapped to the proximal VCFS-REP contained GGT.2–gene 13, which could not be distinguished from GGT.2–gene 11. B, GGT-AMP PCR products were sequenced to distinguish gene 11 from gene 13. The position of the nucleotide sequences refers to GGT.5–gene 6 (Courtay et al. 1997).View Large Image Figure ViewerDownload Hi-res image Download (PPT) The proximal and distal VCFS-REPs have a complex organization (fig. 2). Subsets or subrepeats of markers containing anonymous genomic sequences are grouped together and repeated multiple times in both the proximal and distal VCFS-REPs. In addition, a cluster of genes/pseudogenes, including GGT, is also present within the repeats. To determine the orientation of the subrepeats, genomic DNA was isolated from bacterial clones that mapped to the intervals and was digested with EcoRI. Each of the markers within the subrepeats was used as a probe on Southern blots containing EcoRI-digested clones from the proximal and distal regions. The EcoRI fragments and the corresponding positive markers are designated by a set of numbered brackets (fig. 2). Although most of the markers examined hybridized to the same size fragment in all the clones that were tested, two of them—D22S131 and 599O20Sp6—consistently produced characteristic restriction fragments among the different loci. The sizes of the EcoRI fragments are indicated along with the marker, as depicted in figure 2. By incorporating the Southern blot data into our maps, we were able to distinguish among the subrepeats to definitively assign clones to the correct interval. Furthermore, we determined that the orientation of the subrepeats, which immediately flank the cluster of genes/pseudogenes, is inverted with respect to each other. The region of highest homology between the proximal and distal VCFS-REPs constitutes a 200-kb region containing the tandem cluster of genes/pseudogenes, flanked by a set of inverted subrepeats. The 200-kb size was calculated by addition of the minimum tiling path of clones that constitutes the shaded interval in figure 2. For the proximal VCFS-REP, two clones (PACs 99506 and 699J1) overlap. PAC 995O6 is positive for 28 markers, and PAC 699J1 is positive for 27 markers. Both clones have an average insert size of 120 kb and an average spacing between markers of 4.4 kb (240 kb/55 markers). The proximal shaded interval contains 46 markers, which represents a physical distance of ∼200 kb (46×4.4 kb). For the distal VCFS-REP, the minimal tiling path includes BAC379N11 and PAC413M7. BAC379N11 is positive with 34 markers and is estimated to be 170 kb. PAC413M7 is positive with 32 markers and is estimated to be 120 kb. The average resolution is 4.4 kb (290 kb/66 markers). The distal shaded interval in figure 2 contains 46 markers and is estimated to be 200 kb, the same as for the proximal interval. To assess the extent of homology between the repeats, individual clones that mapped to the proximal and distal breakpoint intervals were fingerprinted by use of EcoRI digestion (fig. 4). The restriction fragments of cosmids, BACs, and PACs, which were positive with a similar set of markers, were directly compared. The restriction patterns were almost identical among the clones from the proximal and distal repeats. These results provided further confirmation of the mapping data, indicating that the organization and composition of the proximal and distal VCFS-REPs were nearly identical over a 200-kb stretch. To determine whether patients with VCFS with the 3-Mb deletion have breakpoints within the repeats, we integrated the genetic markers into the physical map (fig. 2 [fig. 2). Two genetic markers, D22S427 and D22S1638, flank the proximal VCFS-REP. D22S427 is not deleted in patients with VCFS, whereas D22S1638 is deleted in all patients with VCFS with the 3-Mb deletion (Carlson et al. Carlson et al., 1997Carlson C Sirotkin H Pandita R Goldberg R McKie J Wadey R Patanjali SR et al.Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.Am J Hum Genet. 1997; 61: 620-629Abstract Full Text PDF PubMed Scopus (286) Google Scholar), indicating that the proximal deletion breakpoint occurs between these two genetic markers. Another type of repeat, the sc11.1 locus, maps to two regions on 22q11 (Lindsay et al. Lindsay et al., 1993Lindsay EA Halford S Wadey R Scambler PJ Baldini A Molecular cytogenetic characterization of the DiGeorge syndrome region using fluorescence in situ hybridization.Genomics. 1993; 17: 403-407Crossref PubMed Scopus (65) Google Scholar). The more centromeric locus, sc11.1a, is adjacent to the proximal VCFS-REP (fig. 2). Approximately 7% of patients with VCFS with a 22q11 deletion have the same proximal breakpoint as those with a 3-Mb deletion but have a nested distal breakpoint resulting in a 1.5-Mb deletion (Carlson et al. Carlson et al., 1997Carlson C Sirotkin H Pandita R Goldberg R McKie J Wadey R Patanjali SR et al.Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.Am J Hum Genet. 1997; 61: 620-629Abstract Full Text PDF PubMed Scopus (286) Google Scholar). The sc11.1b locus maps to the region adjacent to the 1.5-Mb distal deletion breakpoint interval (Funke et al. Funke et al., 1999Funke B Edelmann L McCain N Pandita RK Ferreira J Merscher S Zohouri M et al.Der(22) syndrome and velo-cardio-facial syndrome/DiGeorge syndrome share a 1.5-Mb region of overlap on chromosome 22q11.Am J Hum Genet. 1999; 64: 747-758Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Both loci, sc11.1a and sc11.1b, are deleted in all patients with VCFS with either the 1.5- or 3-Mb deletion (Lindsay et al. Lindsay et al., 1995Lindsay EA Goldberg R Jurecic V Morrow B Carlson C Kucherlapati RS Shprintzen RJ et al.Velo-cardio-facial syndrome: frequency and extent of 22q11 deletions.Am J Med Genet. 1995; 57: 514-522Crossref PubMed Scopus (115) Google Scholar). Therefore, the proximal deletion breakpoint occurs within the repeat, flanked by D22S427 on the centromeric side and by the sc11.1a locus on the telomeric side. The distal breakpoint occurs between the highly polymorphic genetic markers D22S1709 and D22S308 (fig. 5; Carlson et al. Carlson et al., 1997Carlson C Sirotkin H Pandita R Goldberg R McKie J Wadey R Patanjali SR et al.Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.Am J Hum Genet. 1997; 61: 620-629Abstract Full Text PDF PubMed Scopus (286) Google Scholar). D22S308 maps 520 kb telomeric to the distal end of the repeat (Kawasaki et al. Kawasaki et al., 1995Kawasaki K Minoshima S Schooler K Kudoh J Asakawa S de Jong PJ Shimizu N The organization of the human immunoglobulin lambda gene locus.Genome Res. 1995; 5: 125-135Crossref PubMed Google Scholar). To narrow the breakpoint interval we genotyped several patients with the 3-Mb deletion and their unaffected parents with 336L8(CA), a biallelic marker that contains a CA tandem repeat and that immediately flanks the distal VCFS-REP (fig. 2). The level of heterozygosity is .22 (14/64) among the unaffected individuals and .25 (17/68) for the patients with VCFS. These results show that the breakpoint occurs proximal to 336L8(CA) and, therefore, must lie within the distal VCFS-REP. As part of the physical mapping process, each of the insert ends of the bacterial clones was sequenced and analyzed for homology to known genes (Genbank, Blast Search). We found that a set of five genes/pseudogenes maps to the proximal and distal VCFS-REPs (fig. 2). They include GGT-rel, GGT, V7-rel, POM121-like (POM121L), and BCRL (fig. 2). GGT-rel shares 40% amino acid identity with GGT, and both function as gamma-glutamyl transpeptidases (Heisterkamp et al. Heisterkamp et al., 1991Heisterkamp N Rajpert-De Meyts E Uribe L Forman HJ Groffen J Identification of a human gamma-glutamyl cleaving enzyme related to, but distinct from, gamma-glutamyl transpeptidase.Proc Natl Acad Sci USA. 1991; 88: 6303-6307Crossref PubMed Scopus (69) Google Scholar). The GGT genes that map to the proximal and distal VCFS-REPs are transcribed but contain frameshifts indicating that they do not encode functional products (Collins et al. Collins et al., 1997Collins JE Mungall AJ Badcock KL Fay JM Dunham I The organization of the gamma-glutamyl transferase genes and other low copy repeats in human chromosome 22q11.Genome Res. 1997; 7: 522-531PubMed Google Scholar). The V7-rel gene is related in sequence to V7, a gene that encodes a leukocyte surface protein that participates in T-cell activation and that maps to chromosome 1p13 (Ruegg et al. Ruegg et al., 1995Ruegg CL Rivas A Madani ND Zeitung J Laus R Engleman EG V7, a novel leukocyte surface protein that participates in T cell activation II molecular cloning and characterization of the V7 gene.J Immunol. 1995; 154: 4434-4443PubMed Google Scholar). The POM121L gene product is related to a rat nuclear-membrane protein for which the function is not known (Soderqvist et al. Soderqvist et al., 1996Soderqvist H Jiang WQ Ringertz N Hallberg E Formation of nuclear bodies in cells overexpressing the nuclear pore protein POM121.Exp Cell Res. 1996; 225: 75-84Crossref PubMed Scopus (14) Google Scholar). All four genes map to 22q11, as well as to other chromosomes (Heisterkamp et al. Heisterkamp et al., 1991Heisterkamp N Rajpert-De Meyts E Uribe L Forman HJ Groffen J Identification of a human gamma-glutamyl cleaving enzyme related to, but distinct from, gamma-glutamyl transpeptidase.Proc Natl Acad Sci USA. 1991; 88: 6303-6307Crossref PubMed Scopus (69) Google Scholar; Ruegg et al. Ruegg et al., 1995Ruegg CL Rivas A Madani ND Zeitung J Laus R Engleman EG V7, a novel leukocyte surface protein that participates in T cell activation II molecular cloning and characterization of the V7 gene.J Immunol. 1995; 154: 4434-4443PubMed Google Scholar; Kawasaki et al. Kawasaki et al., 1995Kawasaki K Minoshima S Schooler K Kudoh J Asakawa S de Jong PJ Shimizu N The organization of the human immunoglobulin lambda gene locus.Genome Res. 1995; 5: 125-135Crossref PubMed Google Scholar). In contrast, the BCR and related BCRL genes map only to 22q11 (Budarf et al. Budarf et al., 1988Budarf M Canaani E Emanuel BS Linear order of the four BCR-related loci in 22q11.Genomics. 1988; 3: 168-171Crossref PubMed Scopus (16) Google Scholar). The BCR gene is of particular interest because a BCR/ABL fusion gene product results from a t(9;22) translocation implicated in acute lymphocytic leukemia and chronic myelogenous leukemia (MIM 151410) (de Klein et al. de Klein et al., 1982de Klein A van Kessel AG Grosveld G Bartram CR Hagemeijer A Bootsma D Spurr NK et al.A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukemia.Nature. 1982; 300: 765-767Crossref PubMed Scopus (1022) Google Scholar; Shtivelman et al. Shtivelman et al., 1985Shtivelman E Lifshitz B Gale RP Canaani E Fused transcript of abl and bcr genes in chronic myelogenous leukaemia.Nature. 1985; 315: 550-554Crossref PubMed Scopus (1214) Google Scholar). The presence of highly homologous low-copy repeats at the breakpoints on 22q11 indicates that homologous recombination between the repeats mediates the deletion. To understand the mechanism responsible for generating deletions in 22q11, we performed haplotype analysis on two separate three-generation families of patients with VCFS with the 3-Mb deletion (fig. 5). The positions of the VCFS-REPs, with respect to the genetic markers, is depicted in figure 5. Genetic markers that flank either side of the deletion were inherited from a single chromosome 22 in both cases. For BM103, the chromosome 22q11 region originated from her grandfather, BM110. For BM413, it originated from her grandmother, BM547. These data indicate that in both sporadic cases of VCFS an intrachromosomal homologous recombination event occurred, leading to the 3-Mb deletion. The 22q11 region is prone to rearrangements" @default.
• W2029965540 created "2016-06-24" @default.
• W2029965540 creator A5007646636 @default.
• W2029965540 creator A5029381108 @default.
• W2029965540 creator A5056507943 @default.
• W2029965540 date "1999-04-01" @default.
• W2029965540 modified "2023-10-12" @default.
• W2029965540 title "Low-Copy Repeats Mediate the Common 3-Mb Deletion in Patients with Velo-cardio-facial Syndrome" @default.
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