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ATPase Domain <scp> AFG3L2 </scp> Mutations Alter <scp>OPA1</scp> Processing and Cause Optic Neuropathy
- Source :
- Annals of Neurology, Annals of neurology 88(1), 18-32 (2020). doi:10.1002/ana.25723
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
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.
- Subjects :
- Male
0301 basic medicine
DOA
Gene mutation
medicine.disease_cause
ATP-Dependent Proteases
ATPases Associated with Diverse Cellular Activities
Adolescent
Adult
Aged
Child
Female
GTP Phosphohydrolases
Genetic Testing
High-Throughput Nucleotide Sequencing
Humans
Middle Aged
Mutation
Optic Atrophy
Optic Nerve Diseases
Pedigree
Whole Exome Sequencing
Young Adult
OPA1
genetics [Optic Atrophy]
Optic neuropathy
0302 clinical medicine
genetics [ATPases Associated with Diverse Cellular Activities]
Research Articles
Exome sequencing
Genetics
genetics [Optic Nerve Diseases]
Neurology
Spinocerebellar ataxia
medicine.symptom
Research Article
genetics [GTP Phosphohydrolases]
Spastic gait
Ataxia
Biology
SCA28
03 medical and health sciences
Atrophy
Exome Sequencing
medicine
ddc:610
AFG3L2
medicine.disease
eye diseases
optic neuropathy
030104 developmental biology
genetics [ATP-Dependent Proteases]
Neurology (clinical)
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15318249 and 03645134
- Volume :
- 88
- Database :
- OpenAIRE
- Journal :
- Annals of Neurology
- Accession number :
- edsair.doi.dedup.....46c2c378c78c80511b96cd807a4395b2