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PMID: 17999360 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Type 2 NF1 deletions are highly unusual by virtue of the absence of nonallelic homologous recombination hotspots and an apparent preference for female mitotic recombination.

American journal of human genetics ·Vol. 81 ·No. 6 ·2007-12-00 ·Pages 1201-20

Steinmann K, Cooper DN, Kluwe L, Chuzhanova NA, Senger C, Serra E, Lazaro C, Gilaberte M, Wimmer K, Mautner VF, Kehrer-Sawatzki H

Abstract

Approximately 5% of patients with neurofibromatosis type 1 (NF1) exhibit gross deletions that encompass the NF1 gene and its flanking regions. The breakpoints of the common 1.4-Mb (type 1) deletions are located within low-copy repeats (NF1-REPs) and cluster within a 3.4-kb hotspot of nonallelic homologous recombination (NAHR). Here, we present the first comprehensive breakpoint analysis of type 2 deletions, which are a second type of recurring NF1 gene deletion. Type 2 deletions span 1.2 Mb and are characterized by breakpoints located within the SUZ12 gene and its pseudogene, which closely flank the NF1-REPs. Breakpoint analysis of 13 independent type 2 deletions did not reveal any obvious hotspots of NAHR. However, an overrepresentation of polypyrimidine/polypurine tracts and triplex-forming sequences was noted in the breakpoint regions that could have facilitated NAHR. Intriguingly, all 13 type 2 deletions identified so far are characterized by somatic mosaicism, which indicates a positional preference for mitotic NAHR within the NF1 gene region. Indeed, whereas interchromosomal meiotic NAHR occurs between the NF1-REPs giving rise to type 1 deletions, NAHR during mitosis appears to occur intrachromosomally between the SUZ12 gene and its pseudogene, thereby generating type 2 deletions. Such a clear distinction between the preferred sites of mitotic versus meiotic NAHR is unprecedented in any other genomic disorder induced by the local genomic architecture. Additionally, 12 of the 13 mosaic type 2 deletions were found in females. The marked female preponderance among mosaic type 2 deletions contrasts with the equal sex distribution noted for type 1 and/or atypical NF1 deletions. Although an influence of chromatin structure was strongly suspected, no sex-specific differences in the methylation pattern exhibited by the SUZ12 gene were apparent that could explain the higher rate of mitotic recombination in females.

MeSH Terms
Adolescent Adult Carrier Proteins/genetics Chromosomes, Human, Pair 17 Female Humans Male Mitosis/genetics Mosaicism Neoplasm Proteins Neurofibromatosis 1/genetics Neurofibromin 1/deficiency,genetics Nuclear Proteins/genetics Polycomb Repressive Complex 2 Recombination, Genetic Sequence Deletion Sex Characteristics Transcription Factors
Chemicals
Carrier Proteins Neoplasm Proteins Neurofibromin 1 Nuclear Proteins SUZ12 protein, human Transcription Factors Polycomb Repressive Complex 2
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Steinmann Katharina
Institute of Human Genetics, University of Ulm, Ulm, Germany.
Cooper David N
Kluwe Lan
Chuzhanova Nadia A
Senger Cornelia
Serra Eduard
Lazaro Conxi
Gilaberte Montserrat
Wimmer Katharina
Mautner Viktor-Felix
Kehrer-Sawatzki Hildegard
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
1537-6605
DOI
10.1086/522089
Published
2007-12-00
Epub
2007-00-31
Pages
1201-20
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC2276354
Subset
IM
External Links
PubMed source DOI: 10.1086/522089 PMC Full Text View journal details
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