Abstract
An approx 4-Mb genomic segment on chromosome 17p1 1.2 commonly deleted in 70-80% of patients with the Smith-Magenis syndrome (SMS) is flanked by large, complex, highly identical (approx 98.7%), and directly oriented, proximal (approx 256 kb) and distal (approx 176 kb) low-copy repeats (LCRs), termed SMS-REPs. These LCR copies mediate nonallelic homologous recombination (NAHR), resulting in both SMS deletion and the reciprocal duplication dup(17)(p1 1.2p1 1.2). A third copy, the middle SMS-REP (approx 241 kb) is inverted and located between them. Several additional large LCR17ps have been identified fomented by breakpoint mapping in patients with deletions ascertained because of an SMS phenotype. LCRs in proximal 17p constitute more than 23% of the analyzed genome sequence, approx fourfold higher than predictions based on virtual analysis of the entire human genome. LCRs appear to play a significant role not only in common recurrent deletions and duplications, but also in other rearrangements including unusual sized (i.e., uncommon, recurrent and nonrecurrent) chromosomal deletions, reciprocal translocations, and marker chromosomes. DNA sequence analysis from both common and unusual sized recurrent SMS deletions and common dup(17)(p1 1.2p1 1.2) reveals ′recombination hotspots′ or a remarkable positional preference for strand exchange in NAHR events. Large palindromic LCRs, mapping between proximal and middle SMS-REPs, are responsible for the origin of a recurrent somatic isochromosome i(17q), one of the most common recurrent structural abnormalities observed in human neoplasms, suggesting genome architecture may play arole in mitotic as well as meiotic rearrangements. LCRs in proximal 17p are also prominent features in the genome evolution of this region whereby several serial segmental duplications have played an important role in chromosome evolution accompanying primate speciation.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Pentao L, Wise CA, Chinault AC, Patel PI, Lupski JR. Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nat Genet 1992;2:292–300.
Chance PF, Abbas N, Lensch MW, et al. Two autosomal dominant neuropathies result from reciprocal DNA duplication/deletion of a region on chromosome 17. Hum Mol Genet 1994;3:223–228.
Chen K-S, Manian P, Koeuth T, et al. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat Genet 1997;17:154–163.
Reiter LT, Hastings PJ, Nelis E, De Jonghe P, Van Broeckhoven C, Lupski JR. Human meiotic recombination products revealed by sequencing a hotspot for homologous strand exchange in multiple HNPP deletion patients. Am J Hum Genet 1998;62:1023–1033.
Potocki L, Chen K-S, Park S-S, et al. Molecular mechanism for duplication 17p1 1.2-the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet 2000;24:84–87.
Stankiewicz P, Park S-S, Inoue K, Lupski JR. The evolutionary chromosome translocation 4;19 in Gorilla gorilla is associated with microduplication of the chromosome fragment syntenic to sequences surrounding the human proximal CMT1A-REP. Genome Res 2001;11:1205–1210.
Park S-S, Stankiewicz P, Bi W, et al. Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs. Genome Res 2002;12:729–738.
Bi W, Park S-S, Shaw CJ, Withers MA, Patel PI, Lupski JR. Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p1 1.2. Am J Hum Genet 2003;73:1302–1315.
Barbouti A, Stankiewicz P, Nusbaum C, et al. The breakpoint region of the most common isochromosome, i(17q), in human neoplasia is characterized by a complex genomic architecture with large, palindromic, low-copy repeats. Am J Hum Genet 2004;74:1–10.
Smith AC, McGavran L, Robinson J, et al. Interstitial deletion of (17)(p1 1.2p1 1.2) in nine patients. Am J Med Genet 1986;24:393–414.
Stratton RF, Dobyns WB, Greenberg F, et al. Interstitial deletion of (17)(p11.2p1 1.2): report of six additional patients with a new chromosome deletion syndrome. Am J Med Genet 1986;24:421–432.
Greenberg F, Guzzetta V, Montes de Oca-Luna R, et al. Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2). Am J Hum Genet 1991;49:1207–1218.
Chen K-S, Potocki L, Lupski JR. The Smith-Magenis syndrome [del(17)p11.2]: clinical review and molecular advances. Ment Retard Dev Disabil Res Rev 1996;2:122–129.
Greenberg F, Lewis RA, Potocki L, et al. Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). Am J Med Genet 1996;62:247–254.
Juyal RC, Figuera LE, Hauge X, et al. Molecular analyses of 17p1 1.2 deletions in 62 Smith-Magenis syndrome patients. Am J Hum Genet 1996;58:998–1007.
Bi W, Yan J, Stankiewicz P, et al. Genes in the Smith-Magenis syndrome critical deletion interval on chromosome 17p11.2 and the syntenic region of the mouse. Genome Res 2002;12:713–728.
Trask BJ, Mefford H, van den Engh G, et al. Quantification by flow cytometry of chromosome-17 deletions in Smith-Magenis syndrome patients. Hum Genet 1996;98:710–718.
Vlangos CN, Yim DKC, Elsea SH. Refinement of the Smith-Magenis syndrome critical region to ~950 kb and assessment of 17p11.2 deletions. Are all deletions created equally? Mol Genet Metab 2003;79:134–141.
Stankiewicz P, Shaw CJ, Dapper JD, et al. Genome architecture catalyzes nonrecurrent chromosomal rearrangements. Am J Hum Genet 2003;72:1101–1116.
Slager RE, Newton TL, Vlangos CN, Finucane B, Elsea SH. Mutations inRAI1 associated with Smith-Magenis syndrome. Nat Genet 2003;33:466–468.
Bi W, Saifi GM, Shaw CJ, et al. Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Hum Genet 2004;115:515–524.
Potocki L, Shaw CJ, Stankiewicz P, Lupski JR. Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)]. Genet Med 2003;5:430–434.
Potocki L, Treadwell-Deering D, Krull K, et al. The emerging clinical phenotype of the dup(17)(p11.2p1 1.2) syndrome: the homologous recombination reciprocal of the Smith-Magenis microdeletion. Polish Society of Human Genetics, Gdansk, Poland.
Potocki L, Chen K-S, Koeuth T, et al. DNA rearrangements on both homologs of chromosome 17 in a mildly delayed individual with a family history of autosomal dominant carpal tunnel syndrome. Am J Hum Genet 1999;64:471–478.
Shaw CJ, Bi W, Lupski JR. Genetic proof of unequal meiotic crossovers in reciprocal deletion and duplication of 17p11.2. Am J Hum Genet 2002;71:1072–1081.
Probst FJ, Chen K-S, Zhao Q, et al. A physical map of the mouse shaker-2 region contains many of the genes commonly deleted in Smith-Magenis syndrome (del17p11.2p11.2). Genomics 1999;55–348-352.
Lupski JR. Hotspots of homologous recombination in the human genome: not all homologous sequences are equal. Genome Biol 2004;5:242..
Stankiewicz P, Shaw CJ, Withers M, Inoue K, Lupski JR. Serial segmental duplications during primate evolution result in complex human genome architecture. Genome Res 2004;14:2209–2220.
Shaw CJ, Withers MA, Lupski JR. Uncommon Smith-Magenis syndrome deletions can be recurrent by utilizing alternate LCRs as homologous recombination substrates. Am J Hum Genet 2004;75:75–81.
Shaw CJ, Shaw CA, Yu W, et al. Comparative genomic hybridisation using a proximal 17p BAC/PAC array detects rearrangements responsible for four genomic disorders. J Med Genet 2004;41:113–119.
Shaw CJ, Lupski JR. Non-recurrent 17p11.2 deletions are generated by homologous and non-homologous mechanisms. Hum Genet 2004;116:1–7.
Fioretos T, Strömbeck B, Sandberg T, et al. Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p 11 and is not associated with coding TP53 mutations. Blood 1999;4:225–232.
Scheurlen WG, Schwabe GC, Seranski P, et al. Mapping of the breakpoints on the short arm of chromosome 17 in neoplasms with an i(17q). Genes Chromosomes Cancer 1999;25:230–240.
Stankiewicz P, Inoue K, Bi W, et al. Genomic disorders-genome architecture results in susceptibility to DNA rearrangements causing common human traits. Cold Spring Harb Symp Quant Biol 2003;LXVIII:445–454
Ramirez-Solis R, Liu P, Bradley A. Chromosome engineering in mice. Nature 1995;378:720–724.
Walz K, Caratini-Rivera S, Bi W, et al. Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: phenotypic consequences of gene dosage imbalance. Mol Cell Biol 2003;23:3646–3655.
Walz K, Spencer C, Kaasik K, Lee CC, Lupski JR, Paylor R. Behavioral characterization of mouse models for Smith-Magenis syndrome and dup(17)(p11.2p11.2). Hum Mol Genet 2004;13:367–378.
Yan J, Keener VW, Bi W, et al. Reduced penetrance of craniofacial anomalies as a function of deletion size and genetic background in a chromosome engineered partial mouse model for Smith-Magenis syndrome. Hum Mol Genet 2004;13:2613–2624.
Su H, Wang X, Bradley A. Nested chromosomal deletions induced with retroviral vectors in mice. Nat Genet 2000;24:92–95.
Bi W, Ohyama T, Nakamura H, et al. Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith-Magenis syndrome. Hum. Mol. Genet 2005;14:983–995.
Stankiewicz P, Park S-S, Holder SE, et al. Trisomy 17p10-p12 resulting from a supernumerary marker chromosome derived from chromosome 17: Molecular analysis and delineation of the phenotype. Clin Genet 2001;60:336–344
Shaw CJ, Stankiewicz P, Bien-Willner G, et al. Small marker chromosomes in two patients with segmental aneusomy for proximal 17p. Hum Genet 2004;115:1–7.
Yatsenko SA, Treadwell-Deering D, Krull K, et al. Trisomy 17p10-p12 due to mosaic supernumerary marker chromosome: delineation of molecular breakpoints and clinical phenotype and comparison to other proximal 17p segmental duplications. Am J Med Genet 2005;138A:175–180.
Kiyosawa H, Chance PF. Primate origin of the CMT1A-REP repeat and analysis of a putative transposon-associated recombinational hotspot. Hum Mol Genet 1996;5:745–753.
Reiter LT, Murakami T, Koeuth T, Gibbs RA, Lupski JR. The human COX10 gene is disrupted during homologous recombination between the 24 kb proximal and distal CMT1A-REPs. Hum Mol Genet 1997;6:1595–1603.
Inoue K, Dewar K, Katsanis N, et al. The 1.4-Mb CMT1A duplication/HNPP deletion genomic region reveals unique genome architectural features and provides insights into the recent evolution of new genes. Genome Res 2001;11:1018–1033.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2006 Humana Press Inc., Totowa, NJ
About this chapter
Cite this chapter
Stankiewicz, P., Bi, W., Lupski, J.R. (2006). Smith-Magenis Syndrome Deletion, Reciprocal Duplication dup(17)(p11.2p11.2), and Other Proximal 17p Rearrangements. In: Lupski, J.R., Stankiewicz, P. (eds) Genomic Disorders. Humana Press. https://doi.org/10.1007/978-1-59745-039-3_12
Download citation
DOI: https://doi.org/10.1007/978-1-59745-039-3_12
Publisher Name: Humana Press
Print ISBN: 978-1-58829-559-0
Online ISBN: 978-1-59745-039-3
eBook Packages: MedicineMedicine (R0)