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

B. Hu, M. Wang, R. Castoro, M. Simmons, R. Dortch, R. Yawn, J. Li

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1499-1506
Number of pages8
JournalEuropean Journal of Neurology
Issue number12
StatePublished - Dec 2017


  • apoptosis-inducing factor mitochondrion-associated-1
  • axonal polyneuropathy
  • inherited neuropathy
  • nerve conduction study
  • OXPHOS complex
  • peripheral nerve
  • peripheral nerve magnetic resonance imaging
  • X-linked Charcot-Marie-Tooth disease type-4

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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