Premium
A novel missense mutation in AIFM 1 results in axonal polyneuropathy and misassembly of OXPHOS complexes
Author(s) -
Hu B.,
Wang M.,
Castoro R.,
Simmons M.,
Dortch R.,
Yawn R.,
Li J.
Publication year - 2017
Publication title -
european journal of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 124
eISSN - 1468-1331
pISSN - 1351-5101
DOI - 10.1111/ene.13452
Subject(s) - missense mutation , mitochondrion , mutation , intermembrane space , medicine , neurodegeneration , phenotype , microbiology and biotechnology , biology , genetics , pathology , gene , disease , bacterial outer membrane , escherichia coli
Background and purpose Apoptosis‐inducing factor mitochondrion‐associated‐1 ( AIFM 1) in mitochondria has captured a great deal of attention due to its well‐described function in apoptosis. Mutations in AIFM 1 have resulted in multiple clinical phenotypes, including X‐linked Charcot–Marie–Tooth disease type 4. These syndromes usually involve multiple locations within the nervous system and/or multiple organs. This study describes a novel missense mutation in AIFM 1 and its associated peripheral nerve disease. Methods Patients with AIFM 1 mutation were characterized clinically, electrophysiologically, genetically and by magnetic resonance imaging. The fibroblasts were isolated from the patients to study mitochondrial OXPHOS complexes. Results We identified a family with a novel missense mutation (Phe210Leu) in AIFM 1 who developed an isolated late‐onset axonal polyneuropathy in which the central nervous system and other organs were spared. Interestingly, this Phe210Leu mutation resulted in abnormal assembly of mitochondrial complex I and III , and failed to disrupt AIFM 1 binding with mitochondrial intermembrane space import and assembly protein 40 (MIA40) in the patients’ cells. Deficiency of either AIFM 1 or MIA 40 is known to impair the assembly of mitochondrial complex I and IV . However, levels of both AIFM 1 and MIA 40 were unchanged. Conclusions Phe210Leu mutation in AIFM 1 induces an axonal polyneuropathy that might be contributed by the misassembly of mitochondrial complex I and III. This misassembly appears to be independent of the traditional mechanism via AIFM 1/ MIA 40 deficiency.