Mutational mechanisms in MFN2‐related neuropathy: compound heterozygosity for recessive and semidominant mutations

We describe a 49‐year‐old woman with CMT5 associated with compound heterozygosity for two MFN2 variants, one already reported missense mutation (c.748C>T, p.R250W) and a novel nonsense sequence change (c.1426C>T, p.R476*). Her mother, carrying the p.R250W variant, had very late‐onset minimal axonal neuropathy, whilst the father harboring the nonsense sequence change had neither clinical nor electrophysiological neuropathy. The missense mutation is likely pathogenic according to in silico analyses and a previous report, while the nonsense variant is predicted to behave as a null allele. The p.R250W variant behaves as semi‐dominant by causing only a mild, almost subclinical, neuropathy when heterozygous; the nonsense mutation in the father was phenotypically silent, suggesting that haploinsufficiency for MFN2 is not disease causative, but was deleterious in the daughter who had only one active mutated MFN2 allele.

Source: Journal of the Peripheral Nervous System - August 26, 2015 Category: Neurology Authors: Giuseppe Piscosquito, Paola Saveri, Stefania Magri, Claudia Ciano, Daniela Di Bella, Micaela Milani, Franco Taroni, Davide Pareyson Tags: RESEARCH REPORTS Source Type: research