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

Wolfgang M. Schmidt, S. Lane Rutledge, Rebecca Schüle, Benjamin Mayerhofer, Stephan L Zuchner, Eugen Boltshauser, Reginald E. Bittner

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)855-861
Number of pages7
JournalAmerican Journal of Human Genetics
Volume97
Issue number6
DOIs
StatePublished - Dec 3 2015

Fingerprint

Cerebellar Ataxia
Liver Failure
Peripheral Nervous System Diseases
Atrophy
Mutation
Gait Ataxia
Spinocerebellar Degenerations
Exome
Cerebellar Diseases
Muscular Atrophy
Acute Liver Failure
Golgi Apparatus
Tremor
Ataxia
Optic Nerve
Fibroblasts
Cerebellar Vermis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia. / Schmidt, Wolfgang M.; Rutledge, S. Lane; Schüle, Rebecca; Mayerhofer, Benjamin; Zuchner, Stephan L; Boltshauser, Eugen; Bittner, Reginald E.

In: American Journal of Human Genetics, Vol. 97, No. 6, 03.12.2015, p. 855-861.

Research output: Contribution to journalArticle

Schmidt, Wolfgang M. ; Rutledge, S. Lane ; Schüle, Rebecca ; Mayerhofer, Benjamin ; Zuchner, Stephan L ; Boltshauser, Eugen ; Bittner, Reginald E. / Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia. In: American Journal of Human Genetics. 2015 ; Vol. 97, No. 6. pp. 855-861.
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