Compound heterozygosity for severe and hypomorphicNDUFS2mutations cause non-syndromic LHON-like optic neuropathy
| Autor: | Valérie Serre, Xavier Zanlonghi, Martina G. Ding, Orly Elpeleg, Lucas Bianchi, Klaus Zwicker, Ulrich Brandt, Arnold Munnich, Xavier Gérard, Sylvie Gerber, Marlène Rio, Jean-Michel Rozet, Patrizia Amati-Bonneau, Josseline Kaplan, Sylvain Hanein, Agnès Rötig |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Genetics NDUFS2 Respiratory chain Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] Biology Mitochondrion Compound heterozygosity Genetic analysis Molecular biology Respiratory enzyme 03 medical and health sciences 030104 developmental biology 0302 clinical medicine mitochondrial fusion Gene mapping 030217 neurology & neurosurgery Genetics (clinical) |
| Zdroj: | Journal of Medical Genetics, 54, 346-356 Journal of Medical Genetics, 54, 5, pp. 346-356 |
| ISSN: | 1468-6244 0022-2593 |
| Popis: | Item does not contain fulltext 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. |
| Databáze: | OpenAIRE |
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