title: Homozygous splice mutation in CWF19L1 in a Turkish family with recessive ataxia syndrome.
abstract: OBJECTIVE
  To elucidate the genetic cause of a rare recessive ataxia presented by 2 siblings from a consanguineous Turkish family with a nonprogressive, congenital ataxia with mental retardation of unknown etiology.
  
  
  METHODS
  Whole-exome sequencing was combined with homozygosity mapping, linkage, and expression analysis to identify candidate genes, confirmed by Sanger sequencing. Reverse transcription-PCR and immunoblotting were used to determine the functional consequences of the gene variant. A zebrafish model was developed using morpholino-mediated knockdown.
  
  
  RESULTS
  We identified a homozygous mutation at the invariant +1 position (c.964+1G>A) in intron 9 of the CWF19L1 (complexed with cdc5 protein 19-like 1) gene. This mutation is absent in >6,500 European and African American individuals and 200 Turkish control DNAs. The mutation causes exon skipping, reduction in messenger RNA levels, and protein loss in cell lines of affected individuals. Morpholino-mediated knockdown in a zebrafish model demonstrates that loss of the evolutionarily highly conserved CWF19L1, whose normal biological function is unknown, alters cerebellar morphology and causes movement abnormalities.
  
  
  CONCLUSIONS
  Our results suggest that CWF19L1 mutations may be a novel cause of recessive ataxia with developmental delay. Our research may help with diagnosis, especially in Turkey, identify causes of other ataxias, and may lead to novel therapies.
authors.affiliation: From the Program in Cellular and Molecular Biology (R.B., M.B.), Molecular & Behavioral Neuroscience Institute (R.B., K.M., M.B.), Departments of Human Genetics (J.X., W.P., J.Z.L., M.B.), Neurology (J.J.D.), Pediatrics (J.J.D.), and Psychiatry (M.B.), University of Michigan Medical Center, Ann Arbor; and Department of Neurology (Z.Y.), Division of Child Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkey. J.J.D. is currently affiliated with the Division of Neurology and Program of Genetics and Genome Biology, Hospital for Sick Children, Departments of Pediatrics and Molecular Genetics, University of Toronto, Canada.
authors.forename: Randi
authors.initials: R
authors.lastname: Burns
authors.affiliation: From the Program in Cellular and Molecular Biology (R.B., M.B.), Molecular & Behavioral Neuroscience Institute (R.B., K.M., M.B.), Departments of Human Genetics (J.X., W.P., J.Z.L., M.B.), Neurology (J.J.D.), Pediatrics (J.J.D.), and Psychiatry (M.B.), University of Michigan Medical Center, Ann Arbor; and Department of Neurology (Z.Y.), Division of Child Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkey. J.J.D. is currently affiliated with the Division of Neurology and Program of Genetics and Genome Biology, Hospital for Sick Children, Departments of Pediatrics and Molecular Genetics, University of Toronto, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Majczenko
authors.affiliation: From the Program in Cellular and Molecular Biology (R.B., M.B.), Molecular & Behavioral Neuroscience Institute (R.B., K.M., M.B.), Departments of Human Genetics (J.X., W.P., J.Z.L., M.B.), Neurology (J.J.D.), Pediatrics (J.J.D.), and Psychiatry (M.B.), University of Michigan Medical Center, Ann Arbor; and Department of Neurology (Z.Y.), Division of Child Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkey. J.J.D. is currently affiliated with the Division of Neurology and Program of Genetics and Genome Biology, Hospital for Sick Children, Departments of Pediatrics and Molecular Genetics, University of Toronto, Canada.
authors.forename: Jishu
authors.initials: J
authors.lastname: Xu
authors.affiliation: From the Program in Cellular and Molecular Biology (R.B., M.B.), Molecular & Behavioral Neuroscience Institute (R.B., K.M., M.B.), Departments of Human Genetics (J.X., W.P., J.Z.L., M.B.), Neurology (J.J.D.), Pediatrics (J.J.D.), and Psychiatry (M.B.), University of Michigan Medical Center, Ann Arbor; and Department of Neurology (Z.Y.), Division of Child Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkey. J.J.D. is currently affiliated with the Division of Neurology and Program of Genetics and Genome Biology, Hospital for Sick Children, Departments of Pediatrics and Molecular Genetics, University of Toronto, Canada.
authors.forename: Weiping
authors.initials: W
authors.lastname: Peng
authors.affiliation: From the Program in Cellular and Molecular Biology (R.B., M.B.), Molecular & Behavioral Neuroscience Institute (R.B., K.M., M.B.), Departments of Human Genetics (J.X., W.P., J.Z.L., M.B.), Neurology (J.J.D.), Pediatrics (J.J.D.), and Psychiatry (M.B.), University of Michigan Medical Center, Ann Arbor; and Department of Neurology (Z.Y.), Division of Child Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkey. J.J.D. is currently affiliated with the Division of Neurology and Program of Genetics and Genome Biology, Hospital for Sick Children, Departments of Pediatrics and Molecular Genetics, University of Toronto, Canada.
authors.forename: Zuhal
authors.initials: Z
authors.lastname: Yapici
authors.affiliation: From the Program in Cellular and Molecular Biology (R.B., M.B.), Molecular & Behavioral Neuroscience Institute (R.B., K.M., M.B.), Departments of Human Genetics (J.X., W.P., J.Z.L., M.B.), Neurology (J.J.D.), Pediatrics (J.J.D.), and Psychiatry (M.B.), University of Michigan Medical Center, Ann Arbor; and Department of Neurology (Z.Y.), Division of Child Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkey. J.J.D. is currently affiliated with the Division of Neurology and Program of Genetics and Genome Biology, Hospital for Sick Children, Departments of Pediatrics and Molecular Genetics, University of Toronto, Canada.
authors.forename: James J
authors.initials: JJ
authors.lastname: Dowling
authors.affiliation: From the Program in Cellular and Molecular Biology (R.B., M.B.), Molecular & Behavioral Neuroscience Institute (R.B., K.M., M.B.), Departments of Human Genetics (J.X., W.P., J.Z.L., M.B.), Neurology (J.J.D.), Pediatrics (J.J.D.), and Psychiatry (M.B.), University of Michigan Medical Center, Ann Arbor; and Department of Neurology (Z.Y.), Division of Child Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkey. J.J.D. is currently affiliated with the Division of Neurology and Program of Genetics and Genome Biology, Hospital for Sick Children, Departments of Pediatrics and Molecular Genetics, University of Toronto, Canada.
authors.forename: Jun Z
authors.initials: JZ
authors.lastname: Li
authors.affiliation: From the Program in Cellular and Molecular Biology (R.B., M.B.), Molecular & Behavioral Neuroscience Institute (R.B., K.M., M.B.), Departments of Human Genetics (J.X., W.P., J.Z.L., M.B.), Neurology (J.J.D.), Pediatrics (J.J.D.), and Psychiatry (M.B.), University of Michigan Medical Center, Ann Arbor; and Department of Neurology (Z.Y.), Division of Child Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkey. J.J.D. is currently affiliated with the Division of Neurology and Program of Genetics and Genome Biology, Hospital for Sick Children, Departments of Pediatrics and Molecular Genetics, University of Toronto, Canada. margit@umich.edu.
authors.forename: Margit
authors.initials: M
authors.lastname: Burmeister
mesh_terms: D001259:Ataxia / Q000175:diagnosis / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D014421:Turkey
chemical_list: C000595891:CWF19L1 protein, human; D018797:Cell Cycle Proteins; D022821:RNA Splice Sites