Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. Brain malformations or metabolic disorders are often associated with OS, but other cases remain etiologically unexplained. Here we show that de novo heterozygous mutations in the gene encoding STXBP1, also known as MUNC18-1, which is essential in synaptic vesicle release in multiple species, cause OS. A microdeletion involving STXBP1 and various point mutations, including missense, frameshift, nonsense, and splicing mutations, have been found in individuals with OS. Transcripts associated with frameshift, nonsense, and splicing mutations are likely to be degraded by nonsense mediated mRNA decay. Moreover, STXBP1 proteins harboring missense mutations were unstable compared with the wild-type, and were degraded in Neuroblastoma2A cells. Binding of a mutant protein (p.C180Y) to syntaxin-1A was also significantly impaired. These findings strongly suggest that haploinsufficiency of STXBP1 causes OS. Mutations of STXBP1 also suggest that aberrations of genes involved in synaptic vesicle release might be associated with other types of infantile epilepsy.
Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.