Nonsense-mediated mRNA decay and loss of-function of the protein underlie the X-linked epilepsy associated with the W356X nonsense mutation in SYN1.

"Synapsins are a family of neuronal phosphoproteins associated with the cytosolic surface of synaptic vesicles. Experimental. evidence suggests a role for synapsins in synaptic vesicle clustering and recycling at the presynaptic terminal, as well as in. neuronal development and synaptogenesis. Synapsin knock-out (Syn12\/2) mice display an epileptic phenotype and. mutations in the SYN1 gene have been identified in individuals affected by epilepsy and\/or autism spectrum disorder. We. investigated the impact of the c.1067G.A nonsense transition, the first mutation described in a family affected by X-linked. syndromic epilepsy, on the expression and functional properties of the synapsin I protein. We found that the presence of a. premature termination codon in the human SYN1 transcript renders it susceptible to nonsense-mediated mRNA decay. (NMD). Given that the NMD efficiency is highly variable among individuals and cell types, we investigated also the effects of. expression of the mutant protein and found that it is expressed at lower levels compared to wild-type synapsin I, forms. perinuclear aggregates and is unable to reach presynaptic terminals in mature hippocampal neurons grown in culture.. Taken together, these data indicate that in patients carrying the W3566mutation the function of synapsin I is markedly. impaired, due to both the strongly decreased translation and the altered function of the NMD-escaped protein, and support. the value of Syn12\/2 mice as an experimental model mimicking the human pathology."