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

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Mutations in the mitofusin 2 (MFN2) gene are a primary cause of axonal Charcot-Marie-Tooth disease (CMT2).
• While most MFN2 mutations lead to autosomal dominant CMT2, recessive inheritance patterns have been observed in some families.

Purpose of the Study:

• To investigate early-onset CMT2 in three families with compound heterozygous MFN2 mutations.
• To analyze the impact of these MFN2 mutations on gene transcription.

Main Methods:

• Clinical and electrophysiological assessments of patients and available parents.
• MFN2 DNA sequencing and dosage analysis using multiplex ligation-dependent probe amplification.
• Analysis of MFN2 mRNA transcripts from patient blood lymphocytes.

Main Results:

• Compound heterozygous MFN2 mutations were linked to early-onset CMT2 with variable severity.
• Four novel MFN2 mutations (missense, nonsense, intragenic deletion, 3-bp deletion) and two known missense mutations were identified.
• Transcriptional analysis revealed aberrant splicing and nonsense-mediated decay in affected alleles.

Conclusions:

• MFN2 mutations can cause early-onset CMT2 with apparent recessive inheritance.
• Novel findings include an intragenic MFN2 deletion and evidence of nonsense-mediated decay.
• Asymptomatic carrier parents indicate that single MFN2 null alleles may be nonpathogenic without a second mutation.