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Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations

Polke, JM; Laura, M; Pareyson, D; Taroni, F; Milani, M; Bergamin, G; Gibbons, VS; ... Reilly, MM; + view all (2011) Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations. NEUROLOGY , 77 (2) 168 - 173. 10.1212/WNL.0b013e3182242d4d.

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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. Neurology(R) 2011;77:168-173

Type: Article
Title: Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations
DOI: 10.1212/WNL.0b013e3182242d4d
Keywords: SENSORY NEUROPATHY, HEREDITARY MOTOR, EARLY-CHILDHOOD, MFN2 MUTATIONS, ONSET, PHENOTYPE, TYPE-2
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: http://discovery.ucl.ac.uk/id/eprint/1315532
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