ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

Abstract

Objective Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. Methods We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient‐derived fibroblasts. Results Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype‐modifier variants. All the DOA‐associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28‐associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA‐associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28‐associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission‐inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. Interpretation This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18–32

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

“…Other heterozygous/compound heterozygous mutations in AFG3L2 have been described in isolated cases with nonsyndromic optic atrophy (although not supported by functional studies) [13,14], and in familial syndromic and non-syndromic optic atrophy [15,16]. The present study further demonstrates that heterozygous mutations in AFG3L2 shall be considered as a genetic cause for ADOA in OPA1 and OPA3-negative cases.…”

Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

“…As described above, dysfunctional AFG3L2-paraplegin complex triggers a stress response orchestrated by OMA1 activation [ 74 , 75 ], which, in turn, enhances OPA1 processing leading to an imbalance towards the soluble forms of OPA1 and mitochondrial fragmentation. Accordingly, this has been confirmed in fibroblasts derived from patients carrying AFG3L2 mutations in the ATPase domain and affected by DOA [ 109 , 111 , 112 ]. Interestingly, patients carrying biallelic SPG7 mutations showed hyperfused mitochondria, in contrast to what observed in AFG3L2 mutant fibroblasts [ 114 ].…”

“…Mutations in AFG3L2 and SPG7 have been initially identified as the cause of spinocerebellar ataxia type 28 (SCA28) and spastic ataxia type 5 [ 106 , 107 ], and hereditary spastic paraplegia type- 7 (HSP7) [ 108 ], respectively. More recently, mutations in both these genes have been reported in patients affected by DOA or syndromic diseases with optic atrophy, also including Parkinsonism [ 109 , 110 , 111 , 112 , 113 ]. As described above, dysfunctional AFG3L2-paraplegin complex triggers a stress response orchestrated by OMA1 activation [ 74 , 75 ], which, in turn, enhances OPA1 processing leading to an imbalance towards the soluble forms of OPA1 and mitochondrial fragmentation.…”

Identification of AFG3L2 dominant optic atrophy following reanalysis of clinical exome sequencing

“…However, OPA1 mutations are undetectable in approximately 30% of patients with dominant optic atrophy. 18 Other genes include heterozygous mutations in the OPA3 gene that produce dominant optic atrophy with cataracts and/or deafness (comprising Costeff syndrome or 3-methyl glutaconic aciduria) (OMIM # 258501 ), mutations in the Wolfram gene WFS1 that causes recessive or dominant Wolfram or Wolfram-like syndrome, respectively (OMIM # 222370 and #614296), and the DNM1L, the gene associated with OPA5 encoding DRP1, a protein that is critical in the regulation of mitochondrial fission (OMIM # 610708 ). 18 …”