title: Homozygous p.V116* mutation in C12orf65 results in Leigh syndrome.
abstract: BACKGROUND
  Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder associated with mitochondrial dysfunction. LS is characterised by elevated lactate and pyruvate and bilateral symmetric hyperintense lesions in the basal ganglia, thalamus, brainstem, cerebral white matter or spinal cord on T2-weighted MRI. LS is a genetically heterogeneous disease, and to date mutations in approximately 40 genes related to mitochondrial function have been linked to the disorder.
  
  
  METHODS
  We investigated a pair of female monozygotic twins diagnosed with LS from consanguineous healthy parents of Indian origin. Their common clinical features included optic atrophy, ophthalmoplegia, spastic paraparesis and mild intellectual disability. High-blood lactate and high-intensity signal in the brainstem on T2-weighted MRI were consistent with a clinical diagnosis of LS. To identify the genetic cause of their condition, we performed whole exome sequencing.
  
  
  RESULTS
  We identified a homozygous nonsense mutation in C12orf65 (NM_001143905; c.346delG, p.V116*) in the affected twins. Interestingly, the identical mutation was previously reported in an Indian family with Charcot-Marie Tooth disease type 6, which displayed some overlapping clinical features with the twins.
  
  
  CONCLUSIONS
  We demonstrate that the identical nonsense mutation in C12orf65 can result in different clinical features, suggesting the involvement of unknown modifiers.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Imagawa
authors.affiliation: Paediatric Neurology Unit, Tel Aviv Sourasky Medical Centre, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Aviva
authors.initials: A
authors.lastname: Fattal-Valevski
authors.affiliation: Paediatric Endocrinology Unit, Tel Aviv Sourasky Medical Centre, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ori
authors.initials: O
authors.lastname: Eyal
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D044466:Asian People; D001921:Brain / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D002648:Child; D018389:Codon, Nonsense / Q000235:genetics; D003241:Consanguinity; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D007585:Jews; D007888:Leigh Disease / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D010375:Pedigree; D010454:Peptide Termination Factors / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense; D024101:Mitochondrial Proteins; D010454:Peptide Termination Factors; C551030:MTRFR protein, human
keywords: MITOCHONDRIAL DISORDERS; NEUROGENETICS