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. Epub 2015 Nov 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport
  • Adolescent
  • Base Sequence
  • Cerebellar Ataxia / genetics*
  • Cerebellar Ataxia / pathology
  • DNA-Binding Proteins
  • Exome
  • Female
  • Gene Expression
  • Hepatolenticular Degeneration / genetics*
  • Hepatolenticular Degeneration / pathology
  • Heterozygote
  • Humans
  • Liver Failure / genetics*
  • Liver Failure / pathology
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Peripheral Nervous System Diseases / genetics*
  • Peripheral Nervous System Diseases / pathology
  • Sequence Analysis, DNA
  • Syndrome
  • Transcription Factors / genetics*
  • Young Adult


  • Adaptor Proteins, Vesicular Transport
  • DNA-Binding Proteins
  • SCYL1 protein, human
  • Transcription Factors