title: Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations.
abstract: 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.
authors.affiliation: Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Polke
authors.forename: M
authors.initials: M
authors.lastname: Laurá
authors.forename: D
authors.initials: D
authors.lastname: Pareyson
authors.forename: F
authors.initials: F
authors.lastname: Taroni
authors.forename: M
authors.initials: M
authors.lastname: Milani
authors.forename: G
authors.initials: G
authors.lastname: Bergamin
authors.forename: V S
authors.initials: VS
authors.lastname: Gibbons
authors.forename: H
authors.initials: H
authors.lastname: Houlden
authors.forename: S C
authors.initials: SC
authors.lastname: Chamley
authors.forename: J
authors.initials: J
authors.lastname: Blake
authors.forename: C
authors.initials: C
authors.lastname: Devile
authors.forename: R
authors.initials: R
authors.lastname: Sandford
authors.forename: M G
authors.initials: MG
authors.lastname: Sweeney
authors.forename: M B
authors.initials: MB
authors.lastname: Davis
authors.forename: M M
authors.initials: MM
authors.lastname: Reilly
mesh_terms: D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D005192:Family Health; D005260:Female; D020558:GTP Phosphohydrolases; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human