A novel missense mutation in AIFM1 results in axonal polyneuropathy and misassembly of OXPHOS complexes

• Published in: European journal of neurology Vol. 24; no. 12; pp. 1499 - 1506
• Main Authors: Hu, B., Wang, M., Castoro, R., Simmons, M., Dortch, R., Yawn, R., Li, J.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2017
• Subjects: Apoptosis; Apoptosis Inducing Factor - genetics; Apoptosis-inducing factor; apoptosis‐inducing factor mitochondrion‐associated‐1; Assembly; axonal polyneuropathy; Central nervous system; Charcot-Marie-Tooth disease; Charcot-Marie-Tooth Disease - genetics; Electron transport chain; Female; Fibroblasts; Humans; inherited neuropathy; Magnetic resonance imaging; Male; Missense mutation; Mitochondria; Mitochondria - genetics; Mutation; Mutation, Missense; NADH-ubiquinone oxidoreductase; nerve conduction study; Nervous system; Organs; OXPHOS complex; Patients; Pedigree; peripheral nerve; peripheral nerve magnetic resonance imaging; Phenotype; Polyneuropathy; Protein transport; X‐linked Charcot‐Marie‐Tooth disease type‐4; inherited neuropathy; axonal polyneuropathy; peripheral nerve; apoptosis-inducing factor mitochondrion-associated-1; nerve conduction study; peripheral nerve magnetic resonance imaging; OXPHOS complex; X-linked Charcot-Marie-Tooth disease type-4
• ISSN: 1351-5101; 1468-1331; 1468-1331
• DOI: 10.1111/ene.13452

Background and purpose Apoptosis‐inducing factor mitochondrion‐associated‐1 (AIFM1) in mitochondria has captured a great deal of attention due to its well‐described function in apoptosis. Mutations in AIFM1 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 AIFM1 and its associated peripheral nerve disease. Methods Patients with AIFM1 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 AIFM1 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 AIFM1 binding with mitochondrial intermembrane space import and assembly protein 40 (MIA40) in the patients’ cells. Deficiency of either AIFM1 or MIA40 is known to impair the assembly of mitochondrial complex I and IV. However, levels of both AIFM1 and MIA40 were unchanged. Conclusions Phe210Leu mutation in AIFM1 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 AIFM1/MIA40 deficiency.