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Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy
Author(s) -
Vanni Nicola,
Fruscione Floriana,
Ferlazzo Edoardo,
Striano Pasquale,
Robbiano Angela,
Traverso Monica,
Sander Thomas,
Falace Antonio,
Gazzerro Elisabetta,
Bramanti Placido,
Bielawski Jacek,
Fassio Anna,
Minetti Carlo,
Genton Pierre,
Zara Federico
Publication year - 2014
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24170
Subject(s) - progressive myoclonus epilepsy , endoplasmic reticulum , ceramide , neurodegeneration , unfolded protein response , mutation , downregulation and upregulation , biology , sphingolipid , ceramide synthase , lafora disease , epilepsy , pathogenesis , neuroscience , microbiology and biotechnology , genetics , gene , medicine , phosphorylation , apoptosis , immunology , disease , phosphatase
Objective Alterations of sphingolipid metabolism are implicated in the pathogenesis of many neurodegenerative disorders. Methods We identified a homozygous nonsynonymous mutation in CERS1 , the gene encoding ceramide synthase 1, in 4 siblings affected by a progressive disorder with myoclonic epilepsy and dementia. CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18‐ceramides. Results We demonstrated that the mutation decreases C18‐ceramide levels. In addition, we showed that downregulation of CerS1 in a neuroblastoma cell line triggers ER stress response and induces proapoptotic pathways. Interpretation This study demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans. Ann Neurol 2014;76:206–212