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PMID: 20493460 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability.

American journal of human genetics ·Vol. 86 ·No. 6 ·2010-06-11 ·Pages 892-903

Zhang F, Seeman P, Liu P, Weterman MA, Gonzaga-Jauregui C, Towne CF, Batish SD, De Vriendt E, De Jonghe P, Rautenstrauss B, Krause KH, Khajavi M, Posadka J, Vandenberghe A, Palau F, Van Maldergem L, Baas F, Timmerman V, Lupski JR

Abstract

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.

MeSH Terms
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
Chemicals
Myelin Proteins PMP22 protein, human
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Zhang Feng
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
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
Baas Frank
Timmerman Vincent
Lupski James R
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
1537-6605
DOI
10.1016/j.ajhg.2010.05.001
Published
2010-06-11
Epub
2010-00-20
Pages
892-903
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC3032071
Subset
IM
Grants
NINDS NIH HHS · R01NS058529 · United States
NCRR NIH HHS · M01 RR000188 · United States
NICHD NIH HHS · P30 HD024064 · United States
NINDS NIH HHS · F32 NS010554 · United States
NICHD NIH HHS · P30HD024064 · United States
NINDS NIH HHS · R01 NS058529 · United States
NCRR NIH HHS · M01RR00188 · United States
External Links
PubMed source DOI: 10.1016/j.ajhg.2010.05.001 PMC Full Text View journal details
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