Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy.
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.


CONCLUSIONS
This study demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans.
Department of Neuroscience, Institute G. Gaslini, Genoa, Italy.
Nicola
N
Vanni
Floriana
F
Fruscione
Edoardo
E
Ferlazzo
Pasquale
P
Striano
Angela
A
Robbiano
Monica
M
Traverso
Thomas
T
Sander
Antonio
A
Falace
Elisabetta
E
Gazzerro
Placido
P
Bramanti
Jacek
J
Bielawski
Anna
A
Fassio
Carlo
C
Minetti
Pierre
P
Genton
Federico
F
Zara
D000462:Algeria; D002518:Ceramides / Q000096:biosynthesis*; D003704:Dementia / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics / Q000378:metabolism*; D035781:Siblings; D051049:Sphingosine N-Acyltransferase / Q000235:genetics / Q000378:metabolism*
D002518:Ceramides; D008565:Membrane Proteins; C493790:CERS1 protein, human; D051049:Sphingosine N-Acyltransferase