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• W2000471643 abstract "The constitutional t(11;22) translocation is the only known recurrent non-Robertsonian translocation in humans. Offspring are susceptible to der(22) syndrome, a severe congenital anomaly disorder caused by 3:1 meiotic nondisjunction events. We previously localized the t(11;22) translocation breakpoint to a region on 22q11 within a low-copy repeat termed “LCR22” and within an AT-rich repeat on 11q23. The LCR22s are implicated in mediating different rearrangements on 22q11, leading to velocardiofacial syndrome/DiGeorge syndrome and cat-eye syndrome by homologous recombination mechanisms. The LCR22s contain AT-rich repetitive sequences, suggesting that such repeats may mediate the t(11;22) translocation. To determine the molecular basis of the translocation, we cloned and sequenced the t(11;22) breakpoint in the derivative 11 and 22 chromosomes in 13 unrelated carriers, including two de novo cases and der(22) syndrome offspring. We found that, in all cases examined, the reciprocal exchange occurred between similar AT-rich repeats on both chromosomes 11q23 and 22q11. To understand the mechanism, we examined the sequence of the breakpoint intervals in the derivative chromosomes and compared this with the deduced normal chromosomal sequence. A palindromic AT-rich sequence with a near-perfect hairpin could form, by intrastrand base-pairing, on the parental chromosomes. The sequence of the breakpoint junction in both derivatives indicates that the exchange events occurred at the center of symmetry of the palindromes, and this resulted in small, overlapping staggered deletions in this region among the different carriers. On the basis of previous studies performed in diverse organisms, we hypothesize that double-strand breaks may occur in the center of the palindrome, the tip of the putative hairpin, leading to illegitimate recombination events between similar AT-rich sequences on chromosomes 11 and 22, resulting in deletions and loss of the palindrome, which then could stabilize the DNA structure. The constitutional t(11;22) translocation is the only known recurrent non-Robertsonian translocation in humans. Offspring are susceptible to der(22) syndrome, a severe congenital anomaly disorder caused by 3:1 meiotic nondisjunction events. We previously localized the t(11;22) translocation breakpoint to a region on 22q11 within a low-copy repeat termed “LCR22” and within an AT-rich repeat on 11q23. The LCR22s are implicated in mediating different rearrangements on 22q11, leading to velocardiofacial syndrome/DiGeorge syndrome and cat-eye syndrome by homologous recombination mechanisms. The LCR22s contain AT-rich repetitive sequences, suggesting that such repeats may mediate the t(11;22) translocation. To determine the molecular basis of the translocation, we cloned and sequenced the t(11;22) breakpoint in the derivative 11 and 22 chromosomes in 13 unrelated carriers, including two de novo cases and der(22) syndrome offspring. We found that, in all cases examined, the reciprocal exchange occurred between similar AT-rich repeats on both chromosomes 11q23 and 22q11. To understand the mechanism, we examined the sequence of the breakpoint intervals in the derivative chromosomes and compared this with the deduced normal chromosomal sequence. A palindromic AT-rich sequence with a near-perfect hairpin could form, by intrastrand base-pairing, on the parental chromosomes. The sequence of the breakpoint junction in both derivatives indicates that the exchange events occurred at the center of symmetry of the palindromes, and this resulted in small, overlapping staggered deletions in this region among the different carriers. On the basis of previous studies performed in diverse organisms, we hypothesize that double-strand breaks may occur in the center of the palindrome, the tip of the putative hairpin, leading to illegitimate recombination events between similar AT-rich sequences on chromosomes 11 and 22, resulting in deletions and loss of the palindrome, which then could stabilize the DNA structure. The chromosome 22q11 region is susceptible to rearrangements associated with congenital anomaly disorders, including velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS [MIM 192430/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; 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), cat-eye syndrome (CES [MIM 115470]; Guanti et al. Guanti, 1981Guanti G The aetiology of the cat eye syndrome reconsidered.J Med Genet. 1981; 18: 108-118Crossref PubMed Scopus (24) Google Scholar; Reiss et al. Reiss et al., 1985Reiss JA Weleber RG Brown MG Bangs CD Lovrien EW Magenis RE Tandem duplication of proximal 22q: a cause of cat-eye syndrome.Am J Med Genet. 1985; 20: 165-171Crossref PubMed Scopus (32) Google Scholar) and der(22) syndrome (Fraccaro et al. Fraccaro et al., 1980Fraccaro M Lindsten J Ford CE Iselius L The 11q;22q translocation: a European collaborative analysis of 43 cases.Hum Genet. 1980; 56: 21-51Crossref PubMed Scopus (153) Google Scholar; Zackai and Emanuel Zackai and Emanuel, 1980Zackai EH Emanuel BS Site-specific reciprocal translocation t(11;22)(q23;q11), in several unrelated families with 3:1 meiotic disjunction.Am J Med Genet. 1980; 7: 507-521Crossref PubMed Scopus (121) Google Scholar; Schinzel et al. Schinzel et al., 1981Schinzel A Schmid W Auf der Maur P Moser H Degenhardt KH Geisler M Grubisic A Incomplete trisomy 22. I. Familial 11/22 translocation with 3:1 meiotic disjunction: delineation of a common clinical picture and report of nine new cases from six families.Hum Genet. 1981; 56: 249-262Crossref PubMed Scopus (44) Google Scholar). Most patients with VCFS/DGS have 3-Mb hemizygous deletions of 22q11; a subset have a nested distal deletion endpoint, resulting in a 1.5-Mb deletion, and a few rare patients have unique deletions (Lindsay et al. Lindsay et al., 1995Lindsay EA Goldberg R Jurecic V Morrow B Carlson C Kucherlapati RS Shprintzen RJ Baldini A Velo-cardio-facial syndrome: frequency and extent of 22q11 deletions.Am J Med Genet. 1995; 57: 514-522Crossref PubMed Scopus (115) Google Scholar; Morrow et al. Morrow et al., 1995Morrow B Goldberg R Carlson C Das Gupta R Sirotkin H Collins J Dunham I O'Donnell H Scambler P Shprintzen R Kucherlapati R Molecular definition of the 22q11 deletions in velo-cardio-facial syndrome.Am J Hum Genet. 1995; 56: 1391-1403PubMed Google Scholar; Carlson et al. Carlson et al., 1997Carlson C Sirotkin H Pandita R Goldberg R McKie J Wadey R Patanjali SR Weissman SM Anyane-Yeboa K Warburton D Scambler P Shprintzen R Kucherlapati R Morrow BE 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). Most cases occur sporadically in the population, suggesting that this region is prone to chromosome rearrangements. Physical-mapping studies revealed the presence of low-copy repeat clusters containing genes or pseudogenes, >200 kb in size, at the common 3-Mb deletion endpoints and at a third endpoint, mapping in between the two common ones, containing the 1.5-Mb distal deletion endpoint (Edelmann et al. Edelmann et al., 1999aEdelmann L Pandita RK Morrow BE Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome.Am J Hum Genet. 1999a; 64: 1076-1086Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar Funke et al. Funke et al., 1999Funke B Edelmann L McCain N Pandita R Ferreira J Merscher S Zohouri M Cannizzaro L Shanske A Morrow BE 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; Shaikh et al. Shaikh et al., 1999Shaikh TH Budarf ML Celle L Zackai EH Emanuel BS Clustered 11q23 and 22q11 breakpoints and 3:1 meiotic malsegregation in multiple unrelated t(11;22) families.Am J Hum Genet. 1999; 65: 1595-1607Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). To determine the mechanism causing the deletion, haplotypes were generated in three generations of individuals. Both inter- and intrachromosomal homologous recombination events between the LCR22s mediated the 3-Mb deletion (Baumer et al. Baumer et al., 1998Baumer A Dutly F Balmer D Riegel M Tukel T Krajewska-Walasek M Schinzel AA High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions.Hum Mol Genet. 1998; 7: 887-894Crossref PubMed Scopus (101) Google Scholar; Edelmann et al. Edelmann et al., 1999bEdelmann L Pandita RK Spiteri E Funke B Goldberg R Palanisamy N Chaganti RS Magenis E Shprintzen RJ Morrow BE A common molecular basis for rearrangement disorders on chromosome 22q11.Hum Mol Genet. 1999b; 8: 1157-1167Crossref PubMed Scopus (338) Google Scholar). A family with an interstitial duplication of the same 3-Mb region was identified last year, and haplotype analysis was consistent with an interchromosomal homologous recombination event between the LCR22s (Edelmann et al. Edelmann et al., 1999bEdelmann L Pandita RK Spiteri E Funke B Goldberg R Palanisamy N Chaganti RS Magenis E Shprintzen RJ Morrow BE A common molecular basis for rearrangement disorders on chromosome 22q11.Hum Mol Genet. 1999b; 8: 1157-1167Crossref PubMed Scopus (338) Google Scholar). In addition to these breakpoints, the CES duplication breakpoints resulting in a supernumerary bisatellited chromosome 22 occurred in the same LCR22s as the 3-Mb deletion, resulting in two CES categories, CES-I and CES-II (McTaggart et al. McTaggart et al., 1998McTaggart KE Budarf ML Driscoll DA Emanuel BS Ferreira P McDermid HE Cat eye syndrome chromosome breakpoint clustering: identification of two intervals also associated with 22q11 deletion syndrome breakpoints.Cytogenet Cell Genet. 1998; 81: 222-228Crossref PubMed Scopus (82) Google Scholar; Edelmann et al. Edelmann et al., 1999bEdelmann L Pandita RK Spiteri E Funke B Goldberg R Palanisamy N Chaganti RS Magenis E Shprintzen RJ Morrow BE A common molecular basis for rearrangement disorders on chromosome 22q11.Hum Mol Genet. 1999b; 8: 1157-1167Crossref PubMed Scopus (338) Google Scholar). These results demonstrated that the LCR22s mediate a number of distinct rearrangements on 22q11 by homologous recombination mechanisms leading to congenital anomaly disorders. Meiotic nondisjunction events in carriers of the constitutional t(11;22) translocation result in the severe congenital anomaly disorder, referred to as “der(22) syndrome,” caused by 3:1 meiotic nondisjunction events (Fraccaro et al. Fraccaro et al., 1980Fraccaro M Lindsten J Ford CE Iselius L The 11q;22q translocation: a European collaborative analysis of 43 cases.Hum Genet. 1980; 56: 21-51Crossref PubMed Scopus (153) Google Scholar; Zackai and Emanuel Zackai and Emanuel, 1980Zackai EH Emanuel BS Site-specific reciprocal translocation t(11;22)(q23;q11), in several unrelated families with 3:1 meiotic disjunction.Am J Med Genet. 1980; 7: 507-521Crossref PubMed Scopus (121) Google Scholar). Der(22) syndrome patients carry a der(22) chromosome and are therefore trisomic for 11q23-qter and 22pter-q11. The main clinical findings of der(22) syndrome are moderate mental retardation, mild craniofacial anomalies, and congenital heart defects (Zackai and Emanuel Zackai and Emanuel, 1980Zackai EH Emanuel BS Site-specific reciprocal translocation t(11;22)(q23;q11), in several unrelated families with 3:1 meiotic disjunction.Am J Med Genet. 1980; 7: 507-521Crossref PubMed Scopus (121) Google Scholar; Lin et al. Lin et al., 1986Lin AE Bernar J Chin AJ Sparkes RS Emanuel BS Zackai EH Congenital heart disease in supernumerary der(22),t(11;22) syndrome.Clin Genet. 1986; 29: 269-275Crossref PubMed Scopus (36) Google Scholar). To determine the molecular basis of the reciprocal t(11;22) translocation, the breakpoint intervals on 11q23 and 22q11 were defined. In all carriers examined, the constitutional t(11;22) breakpoint occurred in the same LCR22 as the distal 1.5-Mb deletion in patients with VCFS/DGS (Edelmann et al. Edelmann et al., 1999bEdelmann L Pandita RK Spiteri E Funke B Goldberg R Palanisamy N Chaganti RS Magenis E Shprintzen RJ Morrow BE A common molecular basis for rearrangement disorders on chromosome 22q11.Hum Mol Genet. 1999b; 8: 1157-1167Crossref PubMed Scopus (338) Google Scholar Funke et al. Funke et al., 1999Funke B Edelmann L McCain N Pandita R Ferreira J Merscher S Zohouri M Cannizzaro L Shanske A Morrow BE 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; Shaikh et al. Shaikh et al., 2000Shaikh TH Kurahashi H Saitta SC O'Hare AM Hu P Roe BA Driscoll DA McDonald-McGinn DM Zackai EH Budarf ML Emanuel BS Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis.Hum Mol Genet. 2000; 9: 489-501Crossref PubMed Scopus (398) Google Scholar; Tapia-Paez et al. Tapia-Páez et al., 2000Tapia-Páez I O’Brien KP Kost-Alimova M Sahlen S Kedra D Bruder CE Andersson B Row BA Hu P Imreh S Blennow E Dumanski JP Fine mapping of the constitutional translocation t(11;22)(q23;q11).Hum Genet. 2000; 106: 506-516Crossref PubMed Scopus (22) Google Scholar) referred to as “LCR22-3a” (Dunham et al. Dunham et al., 1999Dunham I Shimizu N Roe BA Chissoe S Hunt AR Collins JE Bruskiewich R et al.The DNA sequence of human chromosome 22.Nature. 1999; 402: 489-495Crossref PubMed Scopus (889) Google Scholar). To narrow the region on 11q23, we generated somatic hybrid cell lines from two unrelated carriers and found that the site of strand exchange occurred in an AT-rich repeat between the genetic markers D11S1340 and APOC3 (Edelmann et al. Edelmann et al., 1999cEdelmann L Spiteri E McCain N Goldberg R Pandita RK Duong S Fox J Blumenthal D Lalani SR Shaffer LG Morrow BE A common breakpoint on 11q23 in carriers of the constitutional t(11;22) translocation.Am J Hum Genet. 1999c; 65: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). The LCR22s also harbor AT-rich repetitive sequence motifs, which we hypothesized could be the region of meiotic exchange. A few years ago, an AT-rich motif was implicated in the novel, reciprocal t(17;22)(q11;q11) translocation in a family with neurofibromatosis type 1 (NF1) (Kehrer-Sawatzki et al. Kehrer-Sawatzki et al., 1997Kehrer-Sawatzki H Haussler J Krone W Bode H Jenne DE Mehnert KU Tummers U Assum G The second case of a t(17;22) in a family with neurofibromatosis type 1: sequence analysis of the breakpoint regions.Hum Genet. 1997; 99: 237-247Crossref PubMed Scopus (75) Google Scholar). The exchange event occurred between an AT-rich repeat within intron 31 of the NF1 gene on chromosome 17 and a similar AT-rich repeat on 22q11 (Kehrer-Sawatzki et al. Kehrer-Sawatzki et al., 1997Kehrer-Sawatzki H Haussler J Krone W Bode H Jenne DE Mehnert KU Tummers U Assum G The second case of a t(17;22) in a family with neurofibromatosis type 1: sequence analysis of the breakpoint regions.Hum Genet. 1997; 99: 237-247Crossref PubMed Scopus (75) Google Scholar), suggesting that there was a common mechanism underlying both the t(11;22) and the t(17;22) translocations. Interestingly, the sequences of the normal chromosomes 17 and 22 surrounding this region consisted of an inverted repeat and therefore was palindromic. Recently, the constitutional t(11;22) translocation was cloned and sequenced (Hill et al. Hill et al., 2000Hill AS Foot NJ Chaplin TL Young BD The most frequent constitutional translocation in humans, the t(11;22)(q23;q11) is due to a highly specific Alu-mediated recombination.Hum Mol Genet. 2000; 9: 1525-1532Crossref PubMed Scopus (35) Google Scholar; Kurahashi et al. Kurahashi et al., 2000aKurahashi H Shaikh TH Hu P Roe BA Emanuel BS Budarf ML Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22).Hum Mol Genet. 2000a; 9: 1665-1670Crossref PubMed Scopus (121) Google ScholarKurahashi et al., 2000bKurahashi H Shaikh TH Zackai EH Celle L Driscoll DA Budarf ML Emanuel BS Tightly clustered 11q23 and 22q11 breakpoints permit PCR-based detection of the recurrent constitutional t(11;22).Am J Hum Genet. 2000b; 67: 763-768Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). In one report (Hill et al. Hill et al., 2000Hill AS Foot NJ Chaplin TL Young BD The most frequent constitutional translocation in humans, the t(11;22)(q23;q11) is due to a highly specific Alu-mediated recombination.Hum Mol Genet. 2000; 9: 1525-1532Crossref PubMed Scopus (35) Google Scholar), the t(11;22) breakpoint in both chromosomes, in five carriers, was mapped to an Alu repeat, and inter-Alu homologous recombination events were the proposed mechanism leading to the translocation. The Alu sequence on chromosome 11 mapped 350 bp proximal to the AT-rich repeat. This result was in conflict with our earlier findings, as well as with the data we present in this report. Two additional reports are in agreement with our finding that the breakpoints occur in palindromic AT-rich repeats (Kurahashi et al. Kurahashi et al., 2000aKurahashi H Shaikh TH Hu P Roe BA Emanuel BS Budarf ML Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22).Hum Mol Genet. 2000a; 9: 1665-1670Crossref PubMed Scopus (121) Google ScholarKurahashi et al., 2000bKurahashi H Shaikh TH Zackai EH Celle L Driscoll DA Budarf ML Emanuel BS Tightly clustered 11q23 and 22q11 breakpoints permit PCR-based detection of the recurrent constitutional t(11;22).Am J Hum Genet. 2000b; 67: 763-768Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar); however, we differ in our interpretation of the data as to the exact region of chromosome breakage and exchange. Characterizing the precise sites of exchange between chromosomes is paramount to understanding the molecular mechanism leading to the translocation. On the basis of studies of palindromic sequences in prokaryotes through mammalian species, we propose that the chromosomal breaks occur in the center of the palindromes, at the tip of the putative hairpins, resulting in illegitimate recombination events producing overlapping staggered deletions. Carriers of the t(11;22) translocation and patients with der(22) syndrome with “BM” codes were ascertained and their conditions diagnosed as described elsewhere (Funke et al. Funke et al., 1999Funke B Edelmann L McCain N Pandita R Ferreira J Merscher S Zohouri M Cannizzaro L Shanske A Morrow BE 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), under an internal review board–approved program. Cell lines obtained for the t(11;22) translocation carriers included GM06229b, GM04403, GM03847, GM03372, and GM06275a, as well as der(22) syndrome patients GM06228, GM04370a, GM03371, and GM00084a, and were purchased from the National Institute of General Medical Science cell repository (Coriell Cell Repositories). Carrier cell lines purchased from the European Collection of Cell Cultures (ECACC) included DD3474, DD0185 (de novo), DD1990, and DD0329. The carrier, BM737—representing a de novo case of the constitutional t(11;22) translocation, as suggested by FISH mapping studies using the N25 probe (Oncor)—was ascertained in our laboratory. To generate haplotypes to rule out nonpaternity, genomic DNA (50 ng) from the carrier (BM737) and the parents (BM738 and 739) was genotyped using the markers D22S427, D22S1638, D22S941, and D22S264, mapping to 22q11, as well as D11S1885, D11S1340, and D11S4127, mapping to 11q23, as described elsewhere (Edelmann et al. Edelmann et al., 1999cEdelmann L Spiteri E McCain N Goldberg R Pandita RK Duong S Fox J Blumenthal D Lalani SR Shaffer LG Morrow BE A common breakpoint on 11q23 in carriers of the constitutional t(11;22) translocation.Am J Hum Genet. 1999c; 65: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Funke et al. Funke et al., 1999Funke B Edelmann L McCain N Pandita R Ferreira J Merscher S Zohouri M Cannizzaro L Shanske A Morrow BE 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). The carrier, V1, was ascertained by the Obstetrics and Gynecology Department at the Albert Einstein College of Medicine. The method used to generate hamster-human somatic hybrid cell lines from the t(11;22) carriers, BM114 and GM06229b, has been described elsewhere (Edelmann et al. Edelmann et al., 1999cEdelmann L Spiteri E McCain N Goldberg R Pandita RK Duong S Fox J Blumenthal D Lalani SR Shaffer LG Morrow BE A common breakpoint on 11q23 in carriers of the constitutional t(11;22) translocation.Am J Hum Genet. 1999c; 65: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). For the PCR-based genotyping experiments, 50 ng of template DNA from each sample was used, under standard reaction conditions, as described elsewhere (Carlson et al. Carlson et al., 1997Carlson C Sirotkin H Pandita R Goldberg R McKie J Wadey R Patanjali SR Weissman SM Anyane-Yeboa K Warburton D Scambler P Shprintzen R Kucherlapati R Morrow BE 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). Genomic DNA was purified from Epstein-Barr–transformed human lymphoblastoid cell lines, human fibroblast cell lines, or hamster-human somatic hybrid cell lines and 10 ug from each sample was digested with the restriction endonucleases, SacI or HindIII. The digested DNA was separated electrophoretically, according to size, on 0.8% agarose gels in TAE buffer and then was transferred onto Hybond N nytran membranes (Amersham). Probes were generated from the PCR products, b1030-4 for the der(11) chromosomes and b1030-6 for the der(22) chromosomes. Primer sequences for these PCR products were as defined elsewhere (Edelmann et al. Edelmann et al., 1999cEdelmann L Spiteri E McCain N Goldberg R Pandita RK Duong S Fox J Blumenthal D Lalani SR Shaffer LG Morrow BE A common breakpoint on 11q23 in carriers of the constitutional t(11;22) translocation.Am J Hum Genet. 1999c; 65: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). The radiolabeled PCR products were used as probes and were hybridized to the membranes at 65°C overnight in standard buffer conditions. Membranes then were washed under stringent conditions in 0.2 × SSC, 0.1% SSC at 65°C for 15 min, with a total of four washes. Autoradiograms were exposed with MS film (Kodak) overnight. A nested PCR approach was used to amplify specific junction fragment products from the der(11) and der(22) chromosomes. To amplify a 1.6-kb product containing the der(11) breakpoint junction fragment, the Expand Long Template PCR system (Roche) was used. Initially, outer primers b1030-5F (Edelmann et al. Edelmann et al., 1999cEdelmann L Spiteri E McCain N Goldberg R Pandita RK Duong S Fox J Blumenthal D Lalani SR Shaffer LG Morrow BE A common breakpoint on 11q23 in carriers of the constitutional t(11;22) translocation.Am J Hum Genet. 1999c; 65: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar) and LCR22-1R (5′-GTCGGGAGAACAAAGACACA-3′) were used, under the following cycling conditions: 94°C for 2 min, followed by30 cycles of 94°C for 30 s, 60°C for 1 min, and 68°C for 2 min, followed by a final extension of 68°C for 7 min. The first-round PCR product was diluted 50-fold and was subjected to a second round of nested PCR. Inner primers b1030-9F (5′-GGGAGAGCATGTAGAGATTG-3′) and AT(26)R1 (Kehrer-Sawatski et al. Kehrer-Sawatzki et al., 1997Kehrer-Sawatzki H Haussler J Krone W Bode H Jenne DE Mehnert KU Tummers U Assum G The second case of a t(17;22) in a family with neurofibromatosis type 1: sequence analysis of the breakpoint regions.Hum Genet. 1997; 99: 237-247Crossref PubMed Scopus (75) Google Scholar) were used to generate an 800-bp PCR product, using the following cycling conditions: 94°C for 2 min, followed by 30 cycles of 94°C for 30 s, 58°C for 1 min, and 68°C for 2 min, followed by a final extension of 68°C for 7 min. The resulting PCR products were isolated from 1% agarose gels (Ultra-Free DA columns, Millipore) and were purified using the Qiagen PCR Purification Kit. To amplify a 1.2-kb product containing the der(22) breakpoint junction fragment, the Expand Long Template PCR system (Roche) was used. Outer primers AT(26)F3 (5′-GGTGTAGTCCCAGTGTGAATT-3′) and b1030-6R (Edelmann et al. Edelmann et al., 1999cEdelmann L Spiteri E McCain N Goldberg R Pandita RK Duong S Fox J Blumenthal D Lalani SR Shaffer LG Morrow BE A common breakpoint on 11q23 in carriers of the constitutional t(11;22) translocation.Am J Hum Genet. 1999c; 65: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar) were used, under the following cycling conditions: 94°C for 2 min, followed by 35 cycles of 94°C for 30 sec, 58°C for 45 sec, and 68°C for 1.5 min, followed by a final extension of 68°C for 10 min. The first-round PCR product was diluted 50-fold and was subjected to a second round of nested PCR. Inner primers AT(26)F1a.2 (5′-TCCCAGTGTGAGTTGGGATT-3′) and b1030-6Frev (5′-CTGAAAGGGCAGAAGTCTTG-3′) were used to generate an 800-bp PCR product, using Platinum Taq polymerase (Gibco) and the supplied buffer, under the following cycling conditions: 94°C for 10 min, followed by 35 cycles of 94°C for 30 sec, 58°C for 45 sec, and 72°C for 45 sec, followed by a final extension of 72°C for 10 min. The resulting PCR products were isolated and were purified as described above for the der(11) products. The purified PCR products were then subjected to automated sequence analysis on ABI 377 sequencing machines. To delineate the chromosomal breakpoints in the somatic hybrid–cell lines created from the unrelated carriers BM114 and GM06229b, we previously performed PCR mapping studies and found that the breakpoints on 22q11 occurred in LCR22-3a, between markers D22S1623 and D22S264, and on 11q23, between the markers D11S1340 and APOC3 (Edelmann et al. Edelmann et al., 1999cEdelmann L Spiteri E McCain N Goldberg R Pandita RK Duong S Fox J Blumenthal D Lalani SR Shaffer LG Morrow BE A common breakpoint on 11q23 in carriers of the constitutional t(11;22) translocation.Am J Hum Genet. 1999c; 65: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). This finding was confirmed recently (Shaikh et al. Shaikh et al., 1999Shaikh TH Budarf ML Celle L Zackai EH Emanuel BS Clustered 11q23 and 22q11 breakpoints and 3:1 meiotic malsegregation in multiple unrelated t(11;22) families.Am J Hum Genet. 1999; 65: 1595-1607Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar; Tapia-Páez et al. Tapia-Páez et al., 2000Tapia-Páez I O’Brien KP Kost-Alimova M Sahlen S Kedra D Bruder CE Andersson B Row BA Hu P Imreh S Blennow E Dumanski JP Fine mapping of the constitutional translocation t(11;22)(q23;q11).Hum Genet. 2000; 106: 506-516Crossref PubMed Scopus (22) Google Scholar). We used a PCR-based approach to systematically divide and narrow the region in the somatic hybrid lines from BM114 and GM 06229b, using the available genomic sequence in the region on 11q23 (GenBank accession number AC007707) (Edelmann et al. Edelmann et al., 1999cEdelmann L Spiteri E McCain N Goldberg R Pandita RK Duong S Fox J Blumenthal D Lalani SR Shaffer LG Morrow BE A common breakpoint on 11q23 in carriers of the constitutional t(11;22) translocation.Am J Hum Genet. 1999c; 65: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). The interval that contained the breakpoint, between the two PCR markers, b1030-5 and b1030-6, was 190 bp and consisted almost entirely of an AT-rich repeat (Edelmann et al. Edelmann et al., 1999cEdelmann L Spiteri E McCain N Goldberg R Pandita RK Duong S Fox J Blumenthal D Lalani SR Shaffer LG Morrow BE A common breakpoint on 11q23 in carriers of the constitutional t(11;22) translocation.Am J Hum Genet. 1999c; 65: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). In a recent report by Hill and colleagues (Hill et al., 2000Hill AS Foot NJ Chaplin TL Young BD The most frequent constitutional translocation in humans, the t(11;22)(q23;q11) is due to a highly specific Alu-mediated recombination.Hum Mol Genet. 2000; 9: 1525-1532Crossref PubMed Scopus (35) Google Scholar), it was proposed that the t(11;22) breakpoint in five carriers occurred in Alu sequences on chromosomes 11 and 22. To demonstrate that the breakpoint was in the AT-rich repeat sequence on 11q23 and not in Alu sequences, PCR mapping studies were performed on the derivative chromosomes and with one of the same carriers, GM06229b, described in the second study (Hill et al. Hill et al., 2000Hill AS Foot NJ Chaplin TL Young BD The most frequent constitutional translocation in humans, the t(11;22)(q23;q11) is due to a highly specific Alu-mediated recombination.Hum Mol Genet. 2000; 9: 1525-1532Crossref PubMed Scopus (35) Google Scholar). To demonstrate the integrity of the derivative and normal chromosomes, we performed PCR mapping st" @default.
• W2000471643 created "2016-06-24" @default.
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• W2000471643 date "2001-01-01" @default.
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• W2000471643 title "AT-Rich Palindromes Mediate the Constitutional t(11;22) Translocation" @default.
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