Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy.

ABSTRACT: De novo heterozygous mutations in STXBP1/Munc18-1 cause early infantile epileptic encephalopathies (EIEE4, OMIM #612164) characterized by infantile epilepsy, developmental delay, intellectual disability, and can include autistic features. We characterized the cellular deficits for an allelic series of seven STXBP1 mutations and developed four mouse models that recapitulate the abnormal EEG activity and cognitive aspects of human STXBP1-encephalopathy. Disease-causing STXBP1 variants supported synaptic transmission to a variable extent on a null background, but had no effect when overexpressed on a heterozygous background. All disease variants had severely decreased protein levels. Together, these cellular studies suggest that impaired protein stability and STXBP1 haploinsufficiency explain

SUBMITTER: Kovacevic J 

PROVIDER: S-EPMC5917748 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature