A novel missense mutation in AIFM 1 results in axonal polyneuropathy and misassembly of OXPHOS complexes

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.