Key Points
-
The most common chromosomal microdeletion syndrome in humans is the chromosome 22 deletion (del22q11). It comprises DiGeorge syndrome, velocardiofacial syndrome and conotruncal anomaly face syndrome, which share a common microdeletion (del22q11) in the proximal long arm of chromosome 22.
-
Approximately 90% of patients have a typically deleted region (TDR) of ∼3Mb, which encompasses ∼30 genes. The lack of variety in deletion size is probably due to the presence of intrachromosomal low-copy repeats (LCRs) flanking the deleted region, which mediate aberrant homologous recombination and unequal crossing-over events between LCR sequences.
-
Despite the genetic homogeneity of the syndrome, the distinct clinical features of the disorder are incompletely penetrant and show variable expressivity. The rare patients who have different deletions or rearrangements in the 22q11 region have not aided the localization of disease genes because some of their rearrangements are non-overlapping.
-
To overcome this paucity of informative human material, mouse models of del22q11 syndrome have been generated using chromosome-engineering techniques to generate deletions in the mouse genome that encompass subsets of the genes deleted in patients. These studies have pointed to genes that might be involved in the del22q11-like cardiovascular defects seen in mice that harbour some of these.
-
Cardiovascular defects in mice carrying del22q11-like deletions were rescued by a transgene that contains Tbx1. Targeted inactivation of Tbx1 showed that its loss produces a phenotype that is similar to a severe del22q11 syndrome phenotype.
-
These chromosome-engineering and gene-knockout studies have identified Tbx1 as a gene that is vital for cardiovascular and pharyngeal development in the mouse.
-
Mutations in the human TBX1 gene have not yet been found in patients that have the clinical features of del22q11 syndrome but not the characteristic deletion, so TBX1 remains a candidate disease gene for the disorder, albeit a tantalizing one.
-
Together these studies have shed light on how disturbed pharyngeal tissue development might underlie many of the clinical features of the del22q11 syndrome, and of the role of Tbx1 in pharyngeal tissue growth and patterning. They indicate that neural crest cells do not have a principal role in the Tbx1 mutant phenotype in the mouse, and are therefore possibly not involved in the pathogenesis of del22q11, although they might be targets of Tbx1 signalling.
Abstract
Identifying the genes that underlie the pathogenesis of chromosome deletion and duplication syndromes is a challenge because the affected chromosomal segment can contain many genes. The identification of genes that are relevant to these disorders often requires the analysis of individuals that carry rare, small deletions, translocations or single-gene mutations. Research into the chromosome 22 deletion (del22q11) syndrome, which encompasses DiGeorge and velocardiofacial syndrome, has taken a different path in recent years, using mouse models to circumvent the paucity of informative human material. These mouse models have provided new insights into the pathogenesis of del22q11 syndrome and have established strategies for research into chromosomal-deletion and -duplication syndromes.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Brewer, C., Holloway, S., Zawalnyski, P., Schinzel, A. & FitzPatrick, D. A chromosomal deletion map of human malformations. Am. J. Hum. Genet. 63, 1153–1159 (1998).
Budarf, M. L. & Emanuel, B. S. Progress in the autosomal segmental aneusomy syndromes (SASs): single or multi-locus disorders? Hum. Mol. Genet. 6, 1657–1665 (1997).A review of some of the more common microdeletion syndromes, with an emphasis on progress towards their molecular characterization.
Li, L. et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nature Genet. 16, 243–251 (1997).
Oda, T. et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nature Genet. 16, 235–242 (1997).
Kishino, T., Lalande, M. & Wagstaff, J. UBE3A/E6-AP mutations cause Angelman syndrome. Nature Genet. 15, 70–73 (1997).
Matsuura, T. et al. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nature Genet. 15, 74–77 (1997).
Frangiskakis, J. M. et al. LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell 86, 59–69 (1996).
Ewart, A. K. et al. A human vascular disorder, supravalvular aortic stenosis, maps to chromosome 7. Proc. Natl Acad. Sci. USA 90, 3226–3230 (1993).
Ewart, A. K. et al. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nature Genet. 5, 11–16 (1993).
Ludecke, H. J. et al. Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer–Giedion syndrome. Hum. Mol. Genet. 4, 31–36 (1995).
Wilson, D. I. et al. Minimum prevalence of chromosome 22q11 deletions. Am. J. Hum. Genet. 55, A975 (1994).
Greenberg, F. et al. Familial DiGeorge syndrome and associated partial monosomy of chromosome 22. Hum. Genet. 65, 317–319 (1984).
Scambler, P. J. et al. Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 339, 1138–1139 (1992).
Driscoll, D. A. et al. Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am. J. Med. Genet. 44, 261–268 (1992).
Burn, J. et al. Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11. J. Med. Genet. 30, 822–824 (1993).
Scambler, P. J. The 22q11 deletion syndromes. Hum. Mol. Genet. 9, 2421–2426 (2000).A general review of del22q11 syndrome that draws together clinical and molecular data from human studies.
Ryan, A. K. et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J. Med. Genet. 34, 798–804 (1997).
McDonald-McGinn, D. M. et al. The 22q11.2 deletion: screening, diagnostic workup, and outcome of results; report on 181 patients. Genet. Test. 1, 99–108 (1997).References 17 and 18 report on the two largest clinical studies completed so far on del22q11 syndrome patients. Significantly, they define the clinical phenotype of patients with the 22q11 deletion rather than just that of DGS.
Lindsay, E. A. et al. Velo-cardio-facial syndrome: frequency and extent of 22q11 deletions. Am. J. Med. Genet. 57, 514–522 (1995).
Carlson, C. et al. Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am. J. Hum. Genet. 61, 620–629 (1997).
Emanuel, B. S. et al. in Etiology and Morphogenesis of Congenital Heart Disease (eds Clark, E., Nazakawa, M. & Takao, A.) 335–339 (Futura, New York, 1999).
Shaikh, T. H. et al. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum. Mol. Genet. 9, 489–501 (2000).
Halford, S. et al. Low-copy-number repeat sequences flank the DiGeorge/velo-cardio-facial syndrome loci at 22q11. Hum. Mol. Genet. 2, 191–196 (1993).
Lindsay, E. A., Halford, S., Wadey, R., Scambler, P. J. & Baldini, A. Molecular cytogenetic characterization of the DiGeorge syndrome region using fluorescence in situ hybridization. Genomics 17, 403–407 (1993).
Edelmann, L., Pandita, R. K. & Morrow, B. E. Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome. Am. J. Hum. Genet. 64, 1076–1086 (1999).
Dunham, I. et al. The DNA sequence of human chromosome 22. Nature 402, 489–495 (1999).
Edelmann, L. et al. A common molecular basis for rearrangement disorders on chromosome 22q11. Hum. Mol. Genet. 8, 1157–1167 (1999).References 22, 25 and 27 report on the identification, mapping and molecular characterization of low-copy repeats in 22q11. Reference 25 suggests models of how aberrant homologous recombination might mediate the formation of some of the chromosomal rearrangements (including del22q11 ) that cluster in this region.
Shaikh, T. H., Kurahashi, H. & Emanuel, B. S. Evolutionarily conserved low copy repeats (LCRs) in 22q11 mediate deletions, duplications, translocations, and genomic instability: an update and literature review. Genet. Med. 3, 6–13 (2001).
McTaggart, K. E. et al. Cat eye syndrome chromosome breakpoint clustering: identification of two intervals also associated with 22q11 deletion syndrome breakpoints. Cytogenet. Cell Genet. 81, 222–228 (1998).
Funke, B. 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. 64, 747–758 (1999).
Shaikh, T. H., Budarf, M. L., Celle, L., Zackai, E. H. & Emanuel, B. S. Clustered 11q23 and 22q11 breakpoints and 3:1 meiotic malsegregation in multiple unrelated t(11;22) families. Am. J. Hum. Genet. 65, 1595–1607 (1999).
de Klein, A. et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 300, 765–767 (1982).
Kehrer-Sawatzki, H. et al. The second case of a t(17;22) in a family with neurofibromatosis type 1: sequence analysis of the breakpoint regions. Hum. Genet. 99, 237–247 (1997).
Perez Jurado, L. A. et al. A duplicated gene in the breakpoint regions of the 7q11.23 Williams–Beuren syndrome deletion encodes the initiator binding protein TFII-I and BAP-135, a phosphorylation target of BTK. Hum. Mol. Genet. 7, 325–334 (1998).
Peoples, R. et al. A physical map, including a BAC/PAC clone contig, of the Williams–Beuren syndrome — deletion region at 7q11.23. Am. J. Hum. Genet. 66, 47–68 (2000).
Chen, K. S. et al. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nature Genet. 17, 154–163 (1997).
Potocki, L. et al. Molecular mechanism for duplication 17p11.2 — the homologous recombination reciprocal of the Smith–Magenis microdeletion. Nature Genet. 24, 84–87 (2000).
Amos-Landgraf, J. M. et al. Chromosome breakage in the Prader–Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. Am. J. Hum. Genet. 65, 370–386 (1999).
Christian, S. L., Fantes, J. A., Mewborn, S. K., Huang, B. & Ledbetter, D. H. Large genomic duplicons map to sites of instability in the Prader–Willi/Angelman syndrome chromosome region (15q11–q13). Hum. Mol. Genet. 8, 1025–1037 (1999).
Chance, P. F. & Fischbeck, K. H. Molecular genetics of Charcot–Marie–Tooth disease and related neuropathies. Hum. Mol. Genet. 3, 1503–1507 (1994).
Bailey, J. A., Yavor, A. M., Massa, H. F., Trask, B. J. & Eichler, E. E. Segmental duplications: organization and impact within the current human genome project assembly. Genome Res. 11, 1005–1017 (2001).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).Part of this report on the human genome sequencing project outlines, in an accessible format, the wealth of information that has been generated on repetitive sequences, including low-copy repeats.
Augusseau, S., Jouk, S., Jalbert, P. & Prieur, M. DiGeorge syndrome and 22q11 rearrangements. Hum. Genet. 74, 206 (1986).
Kurahashi, H. et al. Another critical region for deletion of 22q11: a study of 100 patients. Am. J. Med. Genet. 72, 180–185 (1997).
Amati, F. et al. Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge/velo-cardio-facial syndrome. Eur. J. Hum. Genet. 7, 903–909 (1999).
McQuade, L. et al. Patient with a 22q11.2 deletion with no overlap of the minimal DiGeorge syndrome critical region (MDGCR). Am. J. Med. Genet. 86, 27–33 (1999).
Rauch, A. et al. A novel 22q11.2 microdeletion in DiGeorge syndrome. Am. J. Hum. Genet. 64, 659–666 (1999).
Yamagishi, H., Garg, V., Matsuoka, R., Thomas, T. & Srivastava, D. A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Science 283, 1158–1161 (1999).
Gong, W. et al. A transcription map of the DiGeorge and velo-cardio-facial syndrome minimal critical region on 22q11. Hum. Mol. Genet. 5, 789–800 (1996).
Botta, A., Lindsay, E. A., Jurecic, V. & Baldini, A. Comparative mapping of the DiGeorge syndrome region in mouse shows inconsistent gene order and differential degree of gene conservation. Mamm. Genome 8, 890–895 (1997); erratum in 9, 344 (1998).
Sutherland, H. F., Kim, U. J. & Scambler, P. J. Cloning and comparative mapping of the DiGeorge syndrome critical region in the mouse. Genomics 52, 37–43 (1998).
Puech, A. et al. Comparative mapping of the human 22q11 chromosomal region and the orthologous region in mice reveals complex changes in gene organization. Proc. Natl Acad. Sci. USA 94, 14608–14613 (1997).
Lund, J. et al. Sequence-ready physical map of the mouse chromosome 16 region with conserved synteny to the human velocardiofacial syndrome region on 22q11.2. Mamm. Genome 10, 438–443 (1999).
Lindsay, E. A. et al. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401, 379–383 (1999).This paper describes the first mouse model of del22q11 syndrome.
Kimber, W. L. et al. Deletion of 150 kb in the minimal DiGeorge/velocardiofacial syndrome critical region in mouse. Hum. Mol. Genet. 8, 2229–2237 (1999).
Puech, A. et al. Normal cardiovascular development in mice deficient for 16 genes in 550 kb of the velocardiofacial/DiGeorge syndrome region. Proc. Natl Acad. Sci. USA 97, 10090–10095 (2000).
Gogos, J. A. et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc. Natl Acad. Sci. USA 95, 9991–9996 (1998).
Lindsay, E. A. et al. Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101 (2001).
Merscher, S. et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104, 619–629 (2001).
Taddei, I., Morishima, M., Huynh, T. & Lindsay, E. A. Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/del22q11 syndromes. Proc. Natl Acad. Sci. USA 98, 11428–11431 (2001).
Chapman, D. L. et al. Expression of the T-box family genes, Tbx1–Tbx5, during early mouse development. Dev. Dyn. 206, 379–390 (1996).
Jerome, L. A. & Papaioannou, V. E. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nature Genet. 27, 286–291 (2001).References 58, 59 and 62 describe the identification of mouse Tbx1 as a gene that is crucially important for heart and pharyngeal development.
Robinson, H. B. Jr DiGeorge's or the III–IV pharyngeal pouch syndrome: pathology and a theory of pathogenesis. Perspect. Pediatr. Pathol. 2, 173–206 (1975).
Rohn, R. D. et al. Familial third-fourth pharyngeal pouch syndrome with apparent autosomal dominant transmission. J. Pediatr. 105, 47–51 (1984).
Piotrowski, T. et al. Jaw and branchial arch mutants in zebrafish II: anterior arches and cartilage differentiation. Development 123, 345–356 (1996).
Schilling, T. F. et al. Jaw and branchial arch mutants in zebrafish I: branchial arches. Development 123, 329–344 (1996).
Piotrowski, T. & Nusslein-Volhard, C. The endoderm plays an important role in patterning the segmented pharyngeal region in zebrafish (Danio rerio). Dev. Biol. 225, 339–356 (2000).
Graham, A. & Smith, A. Patterning the pharyngeal arches. Bioessays 23, 54–61 (2001).A comprehensive review of pharyngeal development and the importance of neural crest for this process.
Cleaver, O. & Krieg, P. A. Notochord patterning of the endoderm. Dev. Biol. 234, 1–12 (2001).
Bockman, D. E., Redmond, M. E. & Kirby, M. L. Alteration of early vascular development after ablation of cranial neural crest. Anat. Rec. 225, 209–217 (1989).
Veitch, E., Begbie, J., Schilling, T. F., Smith, M. M. & Graham, A. Pharyngeal arch patterning in the absence of neural crest. Curr. Biol. 9, 1481–1484 (1999).
Van Mierop, L. H. & Kutsche, L. M. Cardiovascular anomalies in DiGeorge syndrome and importance of neural crest as a possible pathogenetic factor. Am. J. Cardiol. 58, 133–137 (1986).
Nishibatake, M., Kirby, M. L. & Van Mierop, L. H. Pathogenesis of persistent truncus arteriosus and dextroposed aorta in the chick embryo after neural crest ablation. Circulation 75, 255–264 (1987).
Bockman, D. E. & Kirby, M. L. Dependence of thymus development on derivatives of the neural crest. Science 223, 498–500 (1984).
Garg, V. et al. Tbx1, a DiGeorge syndrome candidate gene, is regulated by sonic hedgehog during pharyngeal arch development. Dev. Biol. 235, 62–73 (2001).
Chieffo, C. et al. Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Tbx1 gene. Genomics 43, 267–277 (1997).
Campuzano, V. et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423–1427 (1996).
Matsuura, T. et al. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nature Genet. 26, 191–194 (2000).
Guris, D. L., Fantes, J., Tara, D., Druker, B. J. & Imamoto, A. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nature Genet. 27, 293–298 (2001).
Levy, A. et al. Interstitial 22q11 microdeletion excluding the ADU breakpoint in a patient with DiGeorge syndrome. Hum. Mol. Genet. 4, 2417–2419 (1995).
Pfeifer, D. et al. Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region. Am. J. Hum. Genet. 65, 111–124 (1999).
Biben, C. et al. Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5. Circ. Res. 87, 888–895 (2000).
Naf, D. et al. Mouse models for the Wolf–Hirschhorn deletion syndrome. Hum. Mol. Genet. 10, 91–98 (2001).
Nolan, P. M. et al. A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nature Genet. 25, 440–443 (2000).
Hrabe de Angelis, M. H. et al. Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nature Genet. 25, 444–447 (2000).
Zambrowicz, B. P. et al. Disruption and sequence identification of 2,000 genes in mouse embryonic stem cells. Nature 392, 608–611 (1998).
Justice, M. J., Zheng, B., Woychik, R. P. & Bradley, A. Using targeted large deletions and high-efficiency N-ethyl-N-nitrosourea mutagenesis for functional analyses of the mammalian genome. Methods Enzymol. 13, 423–436 (1997).
You, Y. et al. Chromosomal deletion complexes in mice by radiation of embryonic stem cells. Nature Genet. 15, 285–288 (1997).
Ramirez-Solis, R., Liu, P. & Bradley, A. Chromosome engineering in mice. Nature 378, 720–724 (1995).
Smith, A. J. et al. A site-directed chromosomal translocation induced in embryonic stem cells by Cre-loxP recombination. Nature Genet. 9, 376–385 (1995).
Liu, P., Zhang, H., McLellan, A., Vogel, H. & Bradley, A. Embryonic lethality and tumorigenesis caused by segmental aneuploidy on mouse chromosome 11. Genetics 150, 1155–1168 (1998).
Zheng, B., Mills, A. A. & Bradley, A. A system for rapid generation of coat color-tagged knockouts and defined chromosomal rearrangements in mice. Nucleic Acids Res. 27, 2354–2360 (1999).
Zheng, B. et al. Engineering a mouse balancer chromosome. Nature Genet. 22, 375–378 (1999).
Su, H., Wang, X. & Bradley, A. Nested chromosomal deletions induced with retroviral vectors in mice. Nature Genet. 24, 92–95 (2000).This paper shows how retroviral vectors can be used, in conjunction with conventional chromosomal engineering techniques, to rapidly generate numerous chromosomal deletions and duplications of varying sizes.
Schimenti, J. C. et al. Interdigitated deletion complexes on mouse chromosome 5 induced by irradiation of embryonic stem cells. Genome Res. 10, 1043–1050 (2000).
Yu, Y. & Bradley, A. Engineering chromosomal rearrangements in mice. Nature Rev. Genet. 2, 780–790 (2001).
O'Donnell, H., McKeown, C., Gould, C., Morrow, B. & Scambler, P. Detection of an atypical 22q11 deletion that has no overlap with the DiGeorge syndrome critical region. Am. J. Hum. Genet. 60, 1544–1548 (1997).
Demczuk, S., Thomas, G. & Aurias, A. Isolation of a novel gene from the DiGeorge syndrome critical region with homology to Drosophila gdl and to human LAMC1 genes. Hum. Mol. Genet. 5, 633–638 (1996).
Gogos, J. A. et al. The gene encoding proline dehydrogenase modulates sensorimotor gating in mice. Nature Genet. 21, 434–439 (1999).
Demczuk, S. et al. Cloning of a balanced translocation breakpoint in the DiGeorge syndrome critical region and isolation of a novel potential adhesion receptor gene in its vicinity. Hum. Mol. Genet. 4, 551–558 (1995).
Budarf, M. L. et al. Cloning a balanced translocation associated with DiGeorge syndrome and identification of a disrupted candidate gene. Nature Genet. 10, 269–278 (1995).
Rizzu, P. et al. Cloning and comparative mapping of a gene from the commonly deleted region of DiGeorge and velocardiofacial syndromes conserved in C. elegans. Mamm. Genome 7, 639–643 (1996).
Galili, N., Epstein, J. A., Leconte, I., Nayak, S. & Buck, C. A. Gscl, a gene within the minimal DiGeorge critical region, is expressed in primordial germ cells and the developing pons. Dev. Dyn. 212, 86–93 (1998).
Gottlieb, S. et al. The DiGeorge syndrome minimal critical region contains a goosecoid-like (GSCL) homeobox gene that is expressed early in human development. Am. J. Hum. Genet. 60, 1194–1201 (1997).
Heisterkamp, N. et al. Localization of the human mitochondrial citrate transporter protein gene to chromosome 22q11 in the DiGeorge syndrome critical region. Genomics 29, 451–456 (1995).
Sirotkin, H. et al. Isolation of a new clathrin heavy chain gene with muscle-specific expression from the region commonly deleted in velo-cardio-facial syndrome. Hum. Mol. Genet. 5, 617–624 (1996).
Halford, S. et al. Isolation of a putative transcriptional regulator from the region of 22q11 deleted in DiGeorge syndrome, Shprintzen syndrome and familial congenital heart disease. Hum. Mol. Genet. 2, 2099–2107 (1993).
Funke, B. et al. Isolation and characterization of a human gene containing a nuclear localization signal from the critical region for velo-cardio-facial syndrome on 22q11. Genomics 53, 146–154 (1998).
Pizzuti, A. et al. UFD1L, a developmentally expressed ubiquitination gene, is deleted in CATCH 22 syndrome. Hum. Mol. Genet. 6, 259–265 (1997).
Saha, P. et al. The human homolog of Saccharomyces cerevisiae CDC45. J. Biol. Chem. 273, 18205–18209 (1998).
Sirotkin, H. et al. Identification of a new human catenin gene family member (ARVCF) from the region deleted in velo-cardio-facial syndrome. Genomics 41, 75–83 (1997).
Zieger, B., Hashimoto, Y. & Ware, J. Alternative expression of platelet glycoprotein Ib(β) mRNA from an adjacent 5′ gene with an imperfect polyadenylation signal sequence. J. Clin. Invest. 99, 520–525 (1997).
Budarf, M. L. et al. Identification of a patient with Bernard–Soulier syndrome and a deletion in the DiGeorge/velo-cardio-facial chromosomal region in 22q11.2. Hum. Mol. Genet. 4, 763–766 (1995).
Funke, B., Pandita, R. K. & Morrow, B. E. Isolation and characterization of a novel gene containing wd40 repeats from the region deleted in velo-cardio-facial/DiGeorge syndrome on chromosome 22q11. Genomics 73, 264–271 (2001).
Miranda-Vizuete, A., Damdimiopoulos, A. E., Pedrajas, J. R., Gustafsson, J. A. . & Spyrou, G. Human mitochondrial thioredoxin reductase cDNA cloning, expression and genomic organization. Eur. J. Biochem. 261, 405–412 (1999).
Grossman, M. H., Emanuel, B. S. & Budarf, M. L. Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1–q11.2. Genomics 12, 822–825 (1992).
Winqvist, R., Lundstrom, K., Salminen, M., Laatikainen, M. & Ulmanen, I. The human catechol-O-methyltransferase (COMT) gene maps to band q11.2 of chromosome 22 and shows a frequent RFLP with BglI. Cytogenet. Cell Genet. 59, 253–257 (1992).
Halford, S. et al. Isolation of a gene expressed during early embryogenesis from the region of 22q11 commonly deleted in DiGeorge syndrome. Hum. Mol. Genet. 2, 1577–1582 (1993).
Aubry, M. et al. Isolation of a zinc finger gene consistently deleted in DiGeorge syndrome. Hum. Mol. Genet. 2, 1583–1587 (1993).
Kurahashi, H. et al. Isolation and characterization of a novel gene deleted in DiGeorge syndrome. Hum. Mol. Genet. 4, 541–549 (1995).
Author information
Authors and Affiliations
Related links
Related links
DATABASES
Charcot–Marie–Tooth disease, type 1A
conotruncal anomaly face syndrome
Glossary
- HAPLOINSUFFICIENCY
-
When loss of function of one gene copy leads to an abnormal phenotype.
- SEGMENTAL ANEUSOMY
-
Disorder that results from the inappropriate dosage of crucial genes in a genomic segment.
- EXPRESSIVITY
-
The extent to which a particular organ or structure is affected by a particular genotype. Del22q11 syndrome is characterized by variable expressivity because apparently identical deletions can result in mild or severe disease.
- PENETRANCE
-
The proportion of affected individuals among the carriers of a particular genotype. If all individuals with a disease genotype show the disease phenotype, then the disease is said to be completely penetrant.
- SCHIZOAFFECTIVE DISORDER
-
A psychotic illness that comprises both schizophrenia and affective (mood) disorder.
- BIPOLAR DISORDER
-
A mood disorder that is characterized by periodic swings between exaggerated elation and depression.
- PHARYNGEAL ARCHES
-
The tissue that lies between the paired pharyngeal pouches.
- PHARYNGEAL POUCHES
-
Paired embryonic structures formed by the folding of the endodermal lining of the primitive foregut.
- LOW-COPY REPEATS
-
1–200-kb blocks of genomic sequence that are duplicated in one or more locations on a chromosome, and thought to be of recent evolutionary origin because they have very high sequence identity and are absent in closely related species.
- PERSISTENT TRUNCUS ARTERIOSUS
-
A severe heart defect in which a single vessel exits the heart instead of the normal two (the aorta and pulmonary trunk). It reflects the abnormal persistence of an earlier embryonic state.
- POSITIVE SELECTION
-
When a specific chemical is added to a culture medium, the cells that express a positive selectable marker gene, such as the neomycin- or puromycin-resistance genes, survive and are selected for.
- HPRT MINIGENE
-
(hypoxanthine phosphoribosyl transferase (Hprt)). This is divided into two complementary, but non-functional, fragments: 5′Hprt contains exons 1–2 and 3′Hprt contains the remaining exons, 3–9. Each Hprt fragment is linked to a loxP site, and Cre-mediated recombination between them unites the 5′ and 3′ cassettes and restores Hprt activity, which is required for purine biosynthesis and allows desired recombination events to be selected for in HAT (hypoxanthine, aminopterin and thymidine) medium.
- NEGATIVE SELECTION
-
When a specific chemical is added to a culture medium to kill the cells that still express a negative selectable marker gene, such as the herpes simpex virus thymidine kinase gene (HSVtk). Cells that no longer express the marker gene survive.
- HSVTK
-
Herpes simplex virus thymidine kinase (HSVtk) is essential for thymidine-nucleotide biosynthesis by means of a salvage pathway, and is often used as a negative selectable marker in gene targeting.
- AORTICOPULMONARY SEPTUM
-
In early heart development, the heart outflow tract comprises a single tube, the truncus arteriosus, which is later divided into two separate vessels, the aorta and the pulmonary trunk, by the formation of the aorticopulmonary septum.
Rights and permissions
About this article
Cite this article
Lindsay, E. Chromosomal microdeletions: dissecting del22q11 syndrome. Nat Rev Genet 2, 858–868 (2001). https://doi.org/10.1038/35098574
Issue Date:
DOI: https://doi.org/10.1038/35098574
This article is cited by
-
TBX1 targets the miR-200–ZEB2 axis to induce epithelial differentiation and inhibit stem cell properties
Scientific Reports (2022)
-
Polymorphisms in CRYBB2 encoding βB2-crystallin are associated with antisaccade performance and memory function
Translational Psychiatry (2020)
-
Cognition- and circuit-based dysfunction in a mouse model of 22q11.2 microdeletion syndrome: effects of stress
Translational Psychiatry (2020)
-
A loss-of-function mutation p.T52S in RIPPLY3 is a potential predisposing genetic risk factor for Chinese Han conotruncal heart defect patients without the 22q11.2 deletion/duplication
Journal of Translational Medicine (2018)