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Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Chevrollier, Arnaud  ORCID logo  https://orcid.org/0000-0002-5135-6643
Gueguen, Naïg 
Bris, Céline 
Goudenège, David 

Abstract

OBJECTIVE: To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations. METHODS: Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI. RESULTS: We identified 7 and 8 new heterozygous pathogenic variants in SPG7 and AFG3L2. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in AFG3L2 that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the SPG7 variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported. CONCLUSIONS: Our results position SPG7 and AFG3L2 as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.

Description

Keywords

31 Biological Sciences, 32 Biomedical and Clinical Sciences, 3105 Genetics, 3212 Ophthalmology and Optometry, Genetics, Brain Disorders, Neurosciences, Clinical Research, Eye Disease and Disorders of Vision, Neurodegenerative, Rare Diseases, 2.1 Biological and endogenous factors, 2 Aetiology, Neurological

Journal Title

Neurol Genet

Conference Name

Journal ISSN

2376-7839
2376-7839

Volume Title

6

Publisher

Ovid Technologies (Wolters Kluwer Health)