Document Detail

Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations.
MedLine Citation:
PMID:  21715711     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Mutations in mitofusin 2 (MFN2) are the most common cause of axonal Charcot-Marie-Tooth disease (CMT2). Over 50 mutations have been reported, mainly causing autosomal dominant disease, though families with homozygous or compound heterozygous mutations have been described. We present 3 families with early-onset CMT2 associated with compound heterozygous MFN2 mutations. Transcriptional analysis was performed to investigate the effects of the mutations.
METHODS: Patients were examined clinically and electrophysiologically; parents were also examined where available. Genetic investigations included MFN2 DNA sequencing and dosage analysis by multiplex ligation-dependent probe amplification. MFN2 mRNA transcripts from blood lymphocytes were analyzed in 2 families.
RESULTS: Compound heterozygosity for MFN2 mutations was associated with early-onset CMT2 of varying severity between pedigrees. Parents, where examined, were unaffected and were heterozygous for the expected mutations. Four novel mutations were detected (one missense, one nonsense, an intragenic deletion of exons 7 + 8, and a 3-base pair deletion), as well as 2 previously reported missense mutations. Transcriptional analysis demonstrated aberrant splicing of the exonic deletion and indicated nonsense-mediated decay of mutant alleles with premature truncating mutations.
CONCLUSIONS: Our findings confirm that MFN2 mutations can cause early-onset CMT2 with apparent recessive inheritance. Novel genetic findings include an intragenic MFN2 deletion and nonsense-mediated decay. Carrier parents were asymptomatic, suggesting that MFN2 null alleles can be nonpathogenic unless coinherited with another mutation.
J M Polke; M Laurá; D Pareyson; F Taroni; M Milani; G Bergamin; V S Gibbons; H Houlden; S C Chamley; J Blake; C Devile; R Sandford; M G Sweeney; M B Davis; M M Reilly
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-06-29
Journal Detail:
Title:  Neurology     Volume:  77     ISSN:  1526-632X     ISO Abbreviation:  Neurology     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-07-12     Completed Date:  2011-09-09     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0401060     Medline TA:  Neurology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  168-73     Citation Subset:  AIM; IM    
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MeSH Terms
Base Sequence
Charcot-Marie-Tooth Disease / genetics*
Family Health
GTP Phosphohydrolases
Genes, Recessive / genetics*
Membrane Proteins / genetics*
Mitochondrial Proteins / genetics*
Mutation / genetics*
Neural Conduction / genetics*
RNA, Messenger / metabolism
Grant Support
G0601943//Medical Research Council; G0802760//Medical Research Council; GUP04009//Telethon; //Medical Research Council
Reg. No./Substance:
0/Membrane Proteins; 0/Mitochondrial Proteins; 0/RNA, Messenger; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.1.-/MFN2 protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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