title: Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.
abstract: OBJECTIVE
  To identify the genetic cause in 2 families of progressive ataxia, axonal neuropathy, hyporeflexia, and abnormal eye movements, accompanied by progressive hearing loss and ovarian dysgenesis, with a clinical diagnosis of Perrault syndrome.
  
  
  METHODS
  Whole-exome sequencing was performed to identify causative mutations in the 2 affected sisters in each family. Family 1 is of Japanese ancestry, and family 2 is of European ancestry.
  
  
  RESULTS
  In family 1, affected individuals were compound heterozygous for chromosome 10 open reading frame 2 (C10orf2) p.Arg391His and p.Asn585Ser. In family 2, affected individuals were compound heterozygous for C10orf2 p.Trp441Gly and p.Val507Ile. C10orf2 encodes Twinkle, a primase-helicase essential for replication of mitochondrial DNA. Conservation and structural modeling support the causality of the mutations. Twinkle is known also to harbor multiple mutations, nearly all missenses, leading to dominant progressive external ophthalmoplegia type 3 and to recessive mitochondrial DNA depletion syndrome 7, also known as infantile-onset spinocerebellar ataxia.
  
  
  CONCLUSIONS
  Our study identifies Twinkle mutations as a cause of Perrault syndrome accompanied by neurologic features and expands the phenotypic spectrum of recessive disease caused by mutations in Twinkle. The phenotypic heterogeneity of conditions caused by Twinkle mutations and the genetic heterogeneity of Perrault syndrome call for genomic definition of these disorders.
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Morino
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas. hkawakam@hiroshima-u.ac.jp sbpierce@uw.edu.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Pierce
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas.
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Ohsawa
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas.
authors.forename: Marta
authors.initials: M
authors.lastname: Newby
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas.
authors.forename: Keiko
authors.initials: K
authors.lastname: Hiraki-Kamon
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas.
authors.forename: Masahito
authors.initials: M
authors.lastname: Kuramochi
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas.
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Klevit
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas.
authors.forename: Alan
authors.initials: A
authors.lastname: Martin
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Maruyama
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas.
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.affiliation: From the Department of Epidemiology, Research Institute for Radiation Biology and Medicine (H. Morino, Y.M., R.O., K.H.-K., M.K., H.K.), and Department of Clinical Neuroscience & Therapeutics (H. Maruyama), Hiroshima University, Japan; Departments of Medicine (Medical Genetics) and Genome Sciences (S.B.P., T.W., M.K.L., M.-C.K.) and Biochemistry (R.E.K.), University of Washington, Seattle; and Neuromuscular Center (M.N., A.M.), Texas Health Presbyterian Hospital, Dallas. hkawakam@hiroshima-u.ac.jp sbpierce@uw.edu.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Kawakami
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D004265:DNA Helicases / Q000235:genetics*; D005260:Female; D023961:Gonadal Dysgenesis, 46,XX / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009422:Nervous System Diseases / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D024101:Mitochondrial Proteins; D004265:DNA Helicases; C431576:TWNK protein, human