Sylvie Gerber1, Martina G Ding2, Xavier Gérard1, Klaus Zwicker3, Xavier Zanlonghi4, Marlène Rio5, Valérie Serre6,7, Sylvain Hanein1, Arnold Munnich5, Agnès Rotig7, Lucas Bianchi7, Patrizia Amati-Bonneau8, Orly Elpeleg9, Josseline Kaplan1, Ulrich Brandt10,11, Jean-Michel Rozet1. 1. Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France. 2. Molecular Bioenergetics Group, Goethe-University Medical School, Frankfurt am Main, Germany. 3. Institute of Biochemistry I, Goethe-University Medical School, Frankfurt am Main, Germany. 4. Clinique Jules Verne, Nantes, France. 5. Department of Genetics, Necker Hospital, Paris, France. 6. UMR7592 CNRS, Jacques Monod Institute, Paris Diderot University, Paris, France. 7. Laboratory of Genetics in Mitochondrial Diseases, INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France. 8. Department of Biochemistry and Genetics, UMR CNRS 6214-INSERM U1083, CHU Angers, Angers, France. 9. Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 10. Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center, Nijmegen, The Netherlands. 11. Cluster of Excellence Frankfurt Macromolecular Complexes, Goethe-University, Frankfurt am Main, Germany.
Abstract
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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 yeastYarrowia 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 yeastY. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Sarah L Stenton; Marketa Tesarova; Natalia L Sheremet; Claudia B Catarino; Valerio Carelli; Elżbieta Ciara; Kathryn Curry; Martin Engvall; Leah R Fleming; Peter Freisinger; Katarzyna Iwanicka-Pronicka; Elżbieta Jurkiewicz; Thomas Klopstock; Mary K Koenig; Hana Kolářová; Bohdan Kousal; Tatiana Krylova; Chiara La Morgia; Lenka Nosková; Dorota Piekutowska-Abramczuk; Sam N Russo; Viktor Stránecký; Iveta Tóthová; Frank Träisk; Holger Prokisch Journal: Brain Date: 2022-06-03 Impact factor: 15.255
Authors: Sarah L Stenton; Natalia L Sheremet; Claudia B Catarino; Natalia A Andreeva; Zahra Assouline; Piero Barboni; Ortal Barel; Riccardo Berutti; Igor Bychkov; Leonardo Caporali; Mariantonietta Capristo; Michele Carbonelli; Maria L Cascavilla; Peter Charbel Issa; Peter Freisinger; Sylvie Gerber; Daniele Ghezzi; Elisabeth Graf; Juliana Heidler; Maja Hempel; Elise Heon; Yulya S Itkis; Elisheva Javasky; Josseline Kaplan; Robert Kopajtich; Cornelia Kornblum; Reka Kovacs-Nagy; Tatiana D Krylova; Wolfram S Kunz; Chiara La Morgia; Costanza Lamperti; Christina Ludwig; Pedro F Malacarne; Alessandra Maresca; Johannes A Mayr; Jana Meisterknecht; Tatiana A Nevinitsyna; Flavia Palombo; Ben Pode-Shakked; Maria S Shmelkova; Tim M Strom; Francesca Tagliavini; Michal Tzadok; Amelie T van der Ven; Catherine Vignal-Clermont; Matias Wagner; Ekaterina Y Zakharova; Nino V Zhorzholadze; Jean-Michel Rozet; Valerio Carelli; Polina G Tsygankova; Thomas Klopstock; Ilka Wittig; Holger Prokisch Journal: J Clin Invest Date: 2021-03-15 Impact factor: 14.808