Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion
- PMID: 10615134
- DOI: 10.1038/71743
Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion
Abstract
Recombination between repeated sequences at various loci of the human genome are known to give rise to DNA rearrangements associated with many genetic disorders. Perhaps the most extensively characterized genomic region prone to rearrangement is 17p12, which is associated with the peripheral neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP) and Charcot-Marie-Tooth disease type 1A (CMT1A;ref. 2). Homologous recombination between 24-kb flanking repeats, termed CMT1A-REPs, results in a 1.5-Mb deletion that is associated with HNPP, and the reciprocal duplication product is associated with CMT1A (ref. 2). Smith-Magenis syndrome (SMS) is a multiple congenital anomalies, mental retardation syndrome associated with a chromosome 17 microdeletion, del(17)(p11.2p11.2) (ref. 3,4). Most patients (>90%) carry deletions of the same genetic markers and define a common deletion. We report seven unrelated patients with de novo duplications of the same region deleted in SMS. A unique junction fragment, of the same apparent size, was identified in each patient by pulsed field gel electrophoresis (PFGE). Further molecular analyses suggest that the de novo17p11.2 duplication is preferentially paternal in origin, arises from unequal crossing over due to homologous recombination between flanking repeat gene clusters and probably represents the reciprocal recombination product of the SMS deletion. The clinical phenotype resulting from duplication [dup(17)(p11.2p11.2)] is milder than that associated with deficiency of this genomic region. This mechanism of reciprocal deletion and duplication via homologous recombination may not only pertain to the 17p11.2 region, but may also be common to other regions of the genome where interstitial microdeletion syndromes have been defined.
Similar articles
-
17p11.2p12 triplication and del(17)q11.2q12 in a severely affected child with dup(17)p11.2p12 syndrome.Clin Genet. 2007 Jul;72(1):47-58. doi: 10.1111/j.1399-0004.2007.00831.x. Clin Genet. 2007. PMID: 17594399
-
Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome.Nat Genet. 1997 Oct;17(2):154-63. doi: 10.1038/ng1097-154. Nat Genet. 1997. PMID: 9326934
-
Two patients with duplication of 17p11.2: the reciprocal of the Smith-Magenis syndrome deletion?Am J Med Genet. 1996 May 17;63(2):373-7. doi: 10.1002/(SICI)1096-8628(19960517)63:2<373::AID-AJMG9>3.0.CO;2-U. Am J Med Genet. 1996. PMID: 8725788
-
Molecular mechanisms for CMT1A duplication and HNPP deletion.Ann N Y Acad Sci. 1999 Sep 14;883:22-35. Ann N Y Acad Sci. 1999. PMID: 10586226 Review.
-
Overview of hereditary neuropathy with liability to pressure palsies.Ann N Y Acad Sci. 1999 Sep 14;883:14-21. Ann N Y Acad Sci. 1999. PMID: 10586225 Review.
Cited by
-
Prognostic significance of isochromosome 17q in hematologic malignancies.Oncotarget. 2021 Mar 30;12(7):708-718. doi: 10.18632/oncotarget.27914. eCollection 2021 Mar 30. Oncotarget. 2021. PMID: 33868591 Free PMC article.
-
Structural variation mutagenesis of the human genome: Impact on disease and evolution.Environ Mol Mutagen. 2015 Jun;56(5):419-36. doi: 10.1002/em.21943. Epub 2015 Apr 17. Environ Mol Mutagen. 2015. PMID: 25892534 Free PMC article. Review.
-
Tunable, self-contained gene dosage control via proteolytic cleavage of CRISPR-Cas systems.bioRxiv [Preprint]. 2024 Oct 9:2024.10.09.617463. doi: 10.1101/2024.10.09.617463. bioRxiv. 2024. PMID: 39416069 Free PMC article. Preprint.
-
Biology in balance: human diploid genome integrity, gene dosage, and genomic medicine.Trends Genet. 2022 Jun;38(6):554-571. doi: 10.1016/j.tig.2022.03.001. Epub 2022 Apr 18. Trends Genet. 2022. PMID: 35450748 Free PMC article. Review.
-
Mouse chromosome engineering for modeling human disease.Annu Rev Genomics Hum Genet. 2006;7:247-76. doi: 10.1146/annurev.genom.7.080505.115741. Annu Rev Genomics Hum Genet. 2006. PMID: 16824018 Free PMC article. Review.
Publication types
MeSH terms
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous