title: Compound heterozygosity for severe and hypomorphicNDUFS2mutations cause non-syndromic LHON-like optic neuropathy.
abstract: 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.
  
  
  
  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.
  
  
  
  We identified compound heterozygoteNDUFS2disease-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. lipolyticaorthologNUCM, the mutations resulted in absence of complex I and moderate reduction in nicotinamide adenine dinucleotide-ubiquinone oxidoreductase activity, respectively.
  
  
  
  Biallelism forNDUFS2mutations 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 hypomorphicNDUFS2mutations can cause non-syndromic HON. This observation suggests a direct correlation between the severity ofNDUFS2mutations 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.
authors.affiliation: Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gerber
authors.affiliation: Molecular Bioenergetics Group, Goethe-University Medical School, Frankfurt am Main, Germany.
authors.forename: Martina G
authors.initials: MG
authors.lastname: Ding
authors.affiliation: Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Gérard
authors.affiliation: Institute of Biochemistry I, Goethe-University Medical School, Frankfurt am Main, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Zwicker
authors.affiliation: Clinique Jules Verne, Nantes, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Zanlonghi
authors.affiliation: Department of Genetics, Necker Hospital, Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.affiliation: UMR7592 CNRS, Jacques Monod Institute, Paris Diderot University, Paris, France.|Laboratory of Genetics in Mitochondrial Diseases, INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.affiliation: Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Hanein
authors.affiliation: Department of Genetics, Necker Hospital, Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Laboratory of Genetics in Mitochondrial Diseases, INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Rotig
authors.affiliation: Laboratory of Genetics in Mitochondrial Diseases, INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France.
authors.forename: Lucas
authors.initials: L
authors.lastname: Bianchi
authors.affiliation: Department of Biochemistry and Genetics, UMR CNRS 6214-INSERM U1083, CHU Angers, Angers, France.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amati-Bonneau
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France.
authors.forename: Josseline
authors.initials: J
authors.lastname: Kaplan
authors.affiliation: Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center, Nijmegen, The Netherlands.|Cluster of Excellence Frankfurt Macromolecular Complexes, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brandt
authors.affiliation: Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rozet
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D002417:Cattle; D017124:Conserved Sequence / Q000235:genetics; D042967:Electron Transport Complex I / Q000737:chemistry / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000737:chemistry / Q000235:genetics*; D009887:Ophthalmoscopy; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D041623:Tomography, Optical Coherence; D025062:Yarrowia / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C496411:NDUFS2 protein, human
keywords: Complex I; Mitochondria; NDUFS2; Non-syndromic optic neuropathy; Yarrowia lipolytica