title: Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia.
abstract: Hereditary ataxias comprise a group of genetically heterogeneous disorders characterized by clinically variable cerebellar dysfunction and accompanied by involvement of other organ systems. The molecular underpinnings for many of these diseases are widely unknown. Previously, we discovered the disruption of Scyl1 as the molecular basis of the mouse mutant mdf, which is affected by neurogenic muscular atrophy, progressive gait ataxia with tremor, cerebellar vermis atrophy, and optic-nerve thinning. Here, we report on three human individuals, from two unrelated families, who presented with recurrent episodes of acute liver failure in early infancy and are affected by cerebellar vermis atrophy, ataxia, and peripheral neuropathy. By whole-exome sequencing, compound-heterozygous mutations within SCYL1 were identified in all affected individuals. We further show that in SCYL1-deficient human fibroblasts, the Golgi apparatus is massively enlarged, which is in line with the concept that SCYL1 regulates Golgi integrity. Thus, our findings define SCYL1 mutations as the genetic cause of a human hepatocerebellar neuropathy syndrome.
authors.affiliation: Neuromuscular Research Department, Center of Anatomy and Cell Biology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Schmidt
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: S Lane
authors.initials: SL
authors.lastname: Rutledge
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; German Research Center for Neurodegenerative Diseases, University of Tübingen, 72076 Tübingen, Germany; Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Neuromuscular Research Department, Center of Anatomy and Cell Biology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mayerhofer
authors.affiliation: Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: Division of Pediatric Neurology, University Children's Hospital, 8032 Zurich, Switzerland.
authors.forename: Eugen
authors.initials: E
authors.lastname: Boltshauser
authors.affiliation: Neuromuscular Research Department, Center of Anatomy and Cell Biology, Medical University of Vienna, 1090 Vienna, Austria. Electronic address: reginald.bittner@meduniwien.ac.at.
authors.forename: Reginald E
authors.initials: RE
authors.lastname: Bittner
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000293:Adolescent; D001483:Base Sequence; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins; D059472:Exome; D005260:Female; D015870:Gene Expression; D006527:Hepatolenticular Degeneration / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D017093:Liver Failure / Q000235:genetics* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; C464929:SCYL1 protein, human; D014157:Transcription Factors