A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy

Valentina Baderna,Bryony A Thompson,Aamira Huq,Lisa S Kearns,Michael Fahey,Jonathan B Ruddle,Joshua Schultz,Francesca Maltecca

doi:10.1186/s40478-020-00975-w

Abstract

Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed.Here, we describe a family with a strong ADOA history with most family members spanning three generation having childhood onset of visual symptoms. The proband, in addition to optic atrophy, had neurological symptoms consistent with relapsing remitting multiple sclerosis. Clinical exome analysis detected a novel mutation in the AFG3L2 gene (NM_006796.2:c.1010G > A; p.G337E), which segregated with optic atrophy in family members. AFG3L2 is a metalloprotease of the AAA subfamily which exerts quality control in the inner mitochondrial membrane. Interestingly, the identified mutation localizes close to the AAA domain of AFG3L2, while those localized in the proteolytic domain cause dominant spinocerebellar ataxia type 28 (SCA28) or recessive spastic ataxia with epilepsy (SPAX5). Functional studies in patient fibroblasts demonstrate that the p.G337E AFG3L2 mutation strongly destabilizes the long isoforms of OPA1 via OMA hyper-activation and leads to mitochondrial fragmentation, thus explaining the family phenotype. This study widens the clinical spectrum of neurodegenerative diseases caused by AFG3L2 mutations, which shall be considered as genetic cause of ADOA.

Highlights

Autosomal dominant optic atrophy (ADOA) is a genetic condition affecting the retinal ganglion cells (RGCs), whose axons form the optic nerve
The identified p.G337E mutation localizes close to the AAA domain of AFG3L2, in contrast with those causing spinocerebellar ataxia type 28 (SCA28) and Spastic ataxia 5 (SPAX5), which clusterize in the proteolytic domain of the protein
Functional studies of the p.G337E mutation demonstrate its pathogenicity, as it strongly affects the processing of L-OPA1 leading to aberrant mitochondrial fragmentation

Summary

Introduction

ADOA is a genetic condition affecting the retinal ganglion cells (RGCs), whose axons form the optic nerve. We previously demonstrated that loss of AFG3L2 induces hyper-activation of the stress-activated protease OMA1 and leads to excessive OPA1 processing, promoting mitochondrial fragmentation [7]. By clinical exome analysis we identified a novel mutation in AFG3L2 (p.G337E) segregating with optic atrophy within the family.

Results

Conclusion