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PMID: 19324899 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching.

Human molecular genetics ·Vol. 18 ·No. 12 ·2009-06-15 ·Pages 2188-203

Carvalho CM, Zhang F, Liu P, Patel A, Sahoo T, Bacino CA, Shaw C, Peacock S, Pursley A, Tavyev YJ, Ramocki MB, Nawara M, Obersztyn E, Vianna-Morgante AM, Stankiewicz P, Zoghbi HY, Cheung SW, Lupski JR

Abstract

Duplication at the Xq28 band including the MECP2 gene is one of the most common genomic rearrangements identified in neurodevelopmentally delayed males. Such duplications are non-recurrent and can be generated by a non-homologous end joining (NHEJ) mechanism. We investigated the potential mechanisms for MECP2 duplication and examined whether genomic architectural features may play a role in their origin using a custom designed 4-Mb tiling-path oligonucleotide array CGH assay. Each of the 30 patients analyzed showed a unique duplication varying in size from approximately 250 kb to approximately 2.6 Mb. Interestingly, in 77% of these non-recurrent duplications, the distal breakpoints grouped within a 215 kb genomic interval, located 47 kb telomeric to the MECP2 gene. The genomic architecture of this region contains both direct and inverted low-copy repeat (LCR) sequences; this same region undergoes polymorphic structural variation in the general population. Array CGH revealed complex rearrangements in eight patients; in six patients the duplication contained an embedded triplicated segment, and in the other two, stretches of non-duplicated sequences occurred within the duplicated region. Breakpoint junction sequencing was achieved in four duplications and identified an inversion in one patient, demonstrating further complexity. We propose that the presence of LCRs in the vicinity of the MECP2 gene may generate an unstable DNA structure that can induce DNA strand lesions, such as a collapsed fork, and facilitate a Fork Stalling and Template Switching event producing the complex rearrangements involving MECP2.

MeSH Terms
Cohort Studies DNA Breaks DNA Repair Female Gene Duplication Gene Rearrangement Genetic Diseases, X-Linked/genetics Humans Inverted Repeat Sequences Male Methyl-CpG-Binding Protein 2/genetics Templates, Genetic Transcription, Genetic
Chemicals
MECP2 protein, human Methyl-CpG-Binding Protein 2
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Carvalho Claudia M B
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Zhang Feng
Liu Pengfei
Patel Ankita
Sahoo Trilochan
Bacino Carlos A
Shaw Chad
Peacock Sandra
Pursley Amber
Tavyev Y Jane
Ramocki Melissa B
Nawara Magdalena
Obersztyn Ewa
Vianna-Morgante Angela M
Stankiewicz Pawel
Zoghbi Huda Y
Cheung Sau Wai
Lupski James R
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Article Info
Journal
Human molecular genetics
Abbr.
Hum Mol Genet
ISSN
1460-2083
DOI
10.1093/hmg/ddp151
Published
2009-06-15
Epub
2009-00-26
Pages
2188-203
Language
English
Region
England
NLM ID
9208958
PMCID
PMC2685756
Subset
IM
Grants
NINDS NIH HHS · L40 NS060540-01 · United States
NINDS NIH HHS · L40 NS060540 · United States
NINDS NIH HHS · K08 NS062711-01 · United States
NINDS NIH HHS · T32 NS043124 · United States
NCRR NIH HHS · M01RR00188 · United States
NINDS NIH HHS · 1K08NS062711-01 · United States
NINDS NIH HHS · T32 NS43124 · United States
NICHD NIH HHS · HD024064 · United States
NINDS NIH HHS · K08 NS062711 · United States
External Links
PubMed source DOI: 10.1093/hmg/ddp151 PMC Full Text View journal details
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