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Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy
  1. Sylvie Gerber1,
  2. Martina G Ding2,
  3. Xavier Gérard1,
  4. Klaus Zwicker3,
  5. Xavier Zanlonghi4,
  6. Marlène Rio5,
  7. Valérie Serre6,7,
  8. Sylvain Hanein1,
  9. Arnold Munnich5,
  10. Agnès Rotig7,
  11. Lucas Bianchi7,
  12. Patrizia Amati-Bonneau8,
  13. Orly Elpeleg9,
  14. Josseline Kaplan1,
  15. Ulrich Brandt10,11,
  16. Jean-Michel Rozet1
  1. 1Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France
  2. 2Molecular Bioenergetics Group, Goethe-University Medical School, Frankfurt am Main, Germany
  3. 3Institute of Biochemistry I, Goethe-University Medical School, Frankfurt am Main, Germany
  4. 4Clinique Jules Verne, Nantes, France
  5. 5Department of Genetics, Necker Hospital, Paris, France
  6. 6UMR7592 CNRS, Jacques Monod Institute, Paris Diderot University, Paris, France
  7. 7Laboratory of Genetics in Mitochondrial Diseases, INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France
  8. 8Department of Biochemistry and Genetics, UMR CNRS 6214—INSERM U1083, CHU Angers, Angers, France
  9. 9Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  10. 10Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center, Nijmegen, The Netherlands
  11. 11Cluster of Excellence Frankfurt Macromolecular Complexes, Goethe-University, Frankfurt am Main, Germany
  1. Correspondence to Doctor Jean-Michel Rozet, Laboratory of Genetics in Ophthalmology (LGO), Institute of genetic diseases, Imagine, 24 boulevard du Montparnasse, Paris 75015, France; jean-michel.rozet{at}
  2. Professor Ulrich Brandt, Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Centre, Geert Grooteplein-Zuid 10, Route 772, 6525 GA Nijmegen, The Netherlands; Ulrich.brandt{at}


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.

  • Complex I
  • NDUFS2
  • Mitochondria
  • Non-syndromic optic neuropathy
  • Yarrowia lipolytica

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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.