2. Academic Validation
  3. Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia

Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia

  • Am J Hum Genet. 2015 Dec 3;97(6):855-61. doi: 10.1016/j.ajhg.2015.10.011.
Wolfgang M Schmidt 1,  S Lane Rutledge 2,  Rebecca Schüle 3,  Benjamin Mayerhofer 1,  Stephan Züchner 4,  Eugen Boltshauser 5,  Reginald E Bittner 6
Affiliations

Affiliations

  • 1 Neuromuscular Research Department, Center of Anatomy and Cell Biology, Medical University of Vienna, 1090 Vienna, Austria.
  • 2 Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 3 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.
  • 4 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.
  • 5 Division of Pediatric Neurology, University Children's Hospital, 8032 Zurich, Switzerland.
  • 6 Neuromuscular Research Department, Center of Anatomy and Cell Biology, Medical University of Vienna, 1090 Vienna, Austria. Electronic address: reginald.bittner@meduniwien.ac.at.
PMID: 26581903 DOI: 10.1016/j.ajhg.2015.10.011
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.

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