ClinVar

In 6 male members of a large French Canadian family with X-linked epilepsy and/or autism spectrum disorders (EPILX1; 300491), Fassio et al. (2011) identified a hemizygous gln555-to-ter (Q555X) substitution in exon 12 of the SYN1 gene. The mutation, which was found by linkage analysis followed by candidate gene sequencing, was not found in 418 control chromosomes. In vitro functional expression assays showed that the mutation virtually abolished the DE-domain binding to synaptic vesicles. The mutation also abolished or dramatically reduced phosphorylation of the protein and abolished binding to the SH3 domains of interacting proteins. Expression of the mutant protein in Syn1-null hippocampal cells caused impaired axonal elongation and impaired synaptic trafficking by decreasing release of synaptic vesicles, particularly from the readily releasable pool. These findings were consistent with a complete loss of function.

Using lentivirus-infected mouse hippocampal neurons, Lignani et al. (2013) found that the human Q555X mutation interfered with the ability of SYN1 to interact with mouse Syn2 (600755) isoforms and altered the subcellular distribution of SYN1 compared with wildtype SYN1. The Q555X mutation impaired synchronous coupling of synaptic vesicles to vesicle release machinery, reduced the probability of vesicle release in excitatory synapses, and decreased the pool of readily releasable vesicles in inhibitory synapses. The net effect was an excitatory/inhibitory imbalance with network hyperexcitability.