title: Mutational mechanisms in MFN2-related neuropathy: compound heterozygosity for recessive and semidominant mutations.
abstract: Mitofusin-2 (MFN2) mutations are the most common cause of autosomal dominant axonal Charcot-Marie-Tooth disease (CMT, type 2A), sometimes complicated by additional features such as optic atrophy (CMT6) and upper motor neuron involvement (CMT5). Several pathogenic mutations are reported, mainly acting in a dominant fashion, although few sequence variants behaved as recessive or semidominant in rare homozygous or compound heterozygous patients. 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 semidominant 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.
authors: Department of Clinical Neurosciences, Clinic of Central and Peripheral Degenerative Neuropathies Unit, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy.
authors: Giuseppe
authors: G
authors: Piscosquito
authors: Department of Clinical Neurosciences, Clinic of Central and Peripheral Degenerative Neuropathies Unit, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy.
authors: Paola
authors: P
authors: Saveri
authors: Department of Diagnostics and Applied Technology, Unit of Genetics of Neurodegenerative and Metabolic Disease, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy.
authors: Stefania
authors: S
authors: Magri
authors: Department of Diagnostics and Applied Technology, Neurophysiopathology and Epilepsy Centre, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy.
authors: Claudia
authors: C
authors: Ciano
authors: Department of Diagnostics and Applied Technology, Unit of Genetics of Neurodegenerative and Metabolic Disease, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy.
authors: Daniela
authors: D
authors: Di Bella
authors: Department of Diagnostics and Applied Technology, Unit of Genetics of Neurodegenerative and Metabolic Disease, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy.
authors: Micaela
authors: M
authors: Milani
authors: Department of Diagnostics and Applied Technology, Unit of Genetics of Neurodegenerative and Metabolic Disease, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy.
authors: Franco
authors: F
authors: Taroni
authors: Department of Clinical Neurosciences, Clinic of Central and Peripheral Degenerative Neuropathies Unit, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy.
authors: Davide
authors: D
authors: Pareyson
mesh_terms: D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree
chemical_list: D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human
keywords: Charcot-Marie-Tooth disease; mitochondrial dynamic; mitochondrial fusion; mitofusin-2