TY - JOUR
T1 - Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia
AU - Schmidt, Wolfgang M.
AU - Rutledge, S. Lane
AU - Schüle, Rebecca
AU - Mayerhofer, Benjamin
AU - Züchner, Stephan
AU - Boltshauser, Eugen
AU - Bittner, Reginald E.
N1 - Funding Information:
The authors are grateful for the participation of the affected individuals and their parents in this study. The authors thank David R. Kelly, M.D. (Pathologist-in-Chief and Medical Director of Laboratories, Children’s of Alabama, Birmingham, AL and Clinical Professor of Pathology, University of Alabama at Birmingham) for pathological expertise, Lisa Abreu, Feifei Tao, and Cima Saghira (Hussman Institute for Human Genomics, University of Miami) for coordination of clinical data collection and assistance in molecular genetic analysis, and Jennifer Reichbauer (Hertie Institute for Clinical Brain Research, University of Tübingen) for RNA analysis in family 2. The authors thank Ludger Schöls, M.D. (Hertie-Institute for Clinical Brain Research and German Research Center for Neurodegenerative Diseases) for establishing the research cooperation that finally led to identification of the third individual with SCYL1 mutations. This study was supported by the Interdisciplinary Center for Clinical Research Tübingen (grant 1970-0-0 to R.S.), the European Union (grant PIOF-GA-2012-326681 “HSP/CMT genetics” to R.S.), E-RARE grants of the German Ministry for Education and Research to the NEUROLIPID project (01GM1408B to R.S.), and the NIH (grants 5R01NS072248, 1R01NS075764, and 5R01NS054132 to S.Z.).
PY - 2015/12/3
Y1 - 2015/12/3
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2015.10.011
DO - 10.1016/j.ajhg.2015.10.011
M3 - Article
C2 - 26581903
AN - SCOPUS:84952637797
VL - 97
SP - 855
EP - 861
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -