Article (Scientific journals)
Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability.
Zhang, Feng; Seeman, Pavel; Liu, Pengfei et al.
2010In American Journal of Human Genetics, 86 (6), p. 892-903
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Keywords :
Charcot-Marie-Tooth Disease/genetics; Chromosomes, Human, Pair 17; Comparative Genomic Hybridization; DNA Copy Number Variations; Gene Deletion; Gene Duplication; Hereditary Sensory and Motor Neuropathy; Humans; Myelin Proteins/genetics; Paralysis/genetics; Translocation, Genetic
Abstract :
[en] Genomic rearrangements involving the peripheral myelin protein gene (PMP22) in human chromosome 17p12 are associated with neuropathy: duplications cause Charcot-Marie-Tooth disease type 1A (CMT1A), whereas deletions lead to hereditary neuropathy with liability to pressure palsies (HNPP). Our previous studies showed that >99% of these rearrangements are recurrent and mediated by nonallelic homologous recombination (NAHR). Rare copy number variations (CNVs) generated by nonrecurrent rearrangements also exist in 17p12, but their underlying mechanisms are not well understood. We investigated 21 subjects with rare CNVs associated with CMT1A or HNPP by oligonucleotide-based comparative genomic hybridization microarrays and breakpoint sequence analyses, and we identified 17 unique CNVs, including two genomic deletions, ten genomic duplications, two complex rearrangements, and three small exonic deletions. Each of these CNVs includes either the entire PMP22 gene, or exon(s) only, or ultraconserved potential regulatory sequences upstream of PMP22, further supporting the contention that PMP22 is the critical gene mediating the neuropathy phenotypes associated with 17p12 rearrangements. Breakpoint sequence analysis reveals that, different from the predominant NAHR mechanism in recurrent rearrangement, various molecular mechanisms, including nonhomologous end joining, Alu-Alu-mediated recombination, and replication-based mechanisms (e.g., FoSTeS and/or MMBIR), can generate nonrecurrent 17p12 rearrangements associated with neuropathy. We document a multitude of ways in which gene function can be altered by CNVs. Given the characteristics, including small size, structural complexity, and location outside of coding regions, of selected rare CNVs, their identification remains a challenge for genome analysis. Rare CNVs may potentially represent an important portion of "missing heritability" for human diseases.
Disciplines :
Genetics & genetic processes
Author, co-author :
Zhang, Feng
Seeman, Pavel
Liu, Pengfei
Weterman, Marian A J
Gonzaga-Jauregui, Claudia
Towne, Charles F
Batish, Sat Dev
De Vriendt, Els
De Jonghe, Peter
Rautenstrauss, Bernd
Krause, Klaus*-Henning
Khajavi, Mehrdad
Posadka, Jan
Vandenberghe, Antoon
Palau, Francesc
Van Maldergem, Lionel ;  Centre Hospitalier Universitaire de Liège - CHU > Génétique
Baas, Frank
Timmerman, Vincent
Lupski, James R
More authors (9 more) Less
Language :
English
Title :
Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability.
Publication date :
2010
Journal title :
American Journal of Human Genetics
ISSN :
0002-9297
eISSN :
1537-6605
Publisher :
University of Chicago Press, Chicago, United States - Illinois
Volume :
86
Issue :
6
Pages :
892-903
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Available on ORBi :
since 24 January 2011

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