ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

Area of Science:

• Genetics
• Neuro-ophthalmology
• Molecular Biology

Background:

• Dominant optic atrophy (DOA) is the most common inherited optic neuropathy.
• OPA1 mutations account for the majority of DOA cases, but a significant portion remains undiagnosed.

Purpose of the Study:

• To investigate novel genetic causes of optic atrophy in patients negative for OPA1 mutations.
• To elucidate the molecular mechanisms underlying AFG3L2-associated optic neuropathy.

Main Methods:

• Screening of 286 index cases using next-generation sequencing or whole exome sequencing.
• Functional studies in yeast and patient-derived fibroblasts to assess variant pathogenicity.

Main Results:

• Novel AFG3L2 variants were identified in 4% of cases, presenting as dominant or recessive optic neuropathy.
• DOA-associated AFG3L2 mutations cluster in the ATPase domain, distinct from SCA28 mutations.
• Patient fibroblasts exhibited impaired OPA1 processing and mitochondrial fragmentation.

Conclusions:

• AFG3L2 mutations are a significant cause of optic neuropathy, expanding its clinical and genetic spectrum.
• The study reveals distinct molecular mechanisms for AFG3L2-related DOA and spinocerebellar ataxia.
• Dysfunctional OPA1 processing is implicated in the pathogenesis of AFG3L2-associated optic neuropathy.