Background Non-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. The objective of the present study was to identify the molecular cause of non-syndromic LHON-like disease in siblings born to non-consanguineous parents of French origin.
Methods We used a combination of genetic analysis (gene mapping and whole-exome sequencing) in a multiplex family of non-syndromic HON and of functional analyses in patient-derived cultured skin fibroblasts and the yeast Yarrowia lipolytica.
Results We identified compound heterozygote NDUFS2 disease-causing mutations (p.Tyr53Cys; p.Tyr308Cys). Studies using patient-derived cultured skin fibroblasts revealed mildly decreased NDUFS2 and complex I abundance but apparently normal respiratory chain activity. In the yeast Y. lipolytica ortholog NUCM, the mutations resulted in absence of complex I and moderate reduction in nicotinamide adenine dinucleotide-ubiquinone oxidoreductase activity, respectively.
Conclusions Biallelism for NDUFS2 mutations causing severe complex I deficiency has been previously reported to cause Leigh syndrome with optic neuropathy. Our results are consistent with the view that compound heterozygosity for severe and hypomorphic NDUFS2 mutations can cause non-syndromic HON. This observation suggests a direct correlation between the severity of NDUFS2 mutations and that of the disease and further support that there exist a genetic overlap between non-syndromic and syndromic HON due to defective mitochondrial function.
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SG and MGD contributed equally.
Contributors Conceived and designed the experiments: UB, J-MR. Performed the experiments: SG, MGD, XG, KZ, PA-B, SH, LB. Analysed the data: SG, MGD, XG, KZ, XZ, MR, VS, SH, LB, AM, AR. PA-B, Contributed reagents/materials/analysis tools: XZ, OE. Wrote the paper: UB, J-MR.
Funding This work was supported by grants from the Fondation pour la Recherche Médicale (FRM Grant DPM20121125556 to J-MR), the Association Retina France (Grant to JK) and the Excellence Initiative of the German Federal and State Governments (EXC 115 to UB).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Comité de Protection des Personnes Ile-de-France II.
Provenance and peer review Not commissioned; externally peer reviewed.
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