SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function.

Area of Science:

• Neurogenetics
• Molecular Neuroscience
• Synaptic Biology

Background:

• Autism spectrum disorders (ASDs) and epilepsy share genetic links, often involving synaptic function.
• Synapsin 1 (SYN1) is an X-linked gene crucial for regulating neurotransmitter release and synaptogenesis.

Purpose of the Study:

• To investigate the role of synapsin 1 (SYN1) gene mutations in the pathogenesis of autism spectrum disorders (ASDs) and epilepsy.
• To identify specific SYN1 mutations and their functional consequences on synaptic function.

Main Methods:

• Genetic analysis of a French-Canadian family with segregating ASDs and epilepsy.
• Characterization of SYN1 mutations (Q555X, A51G, A550T, T567A) in patient cohorts.
• Functional studies using synapsin I knockout (KO) neurons expressing wild-type and mutant human SYN1.

Main Results:

• A Q555X nonsense mutation in SYN1 was identified in all affected individuals of a large French-Canadian family.
• Additional SYN1 mutations were found in 1.0% of French-Canadian individuals with autism and 3.5% with epilepsy.
• D-domain SYN1 mutants impaired synaptic vesicle pool size and trafficking in KO neurons; Q555X affected phosphorylation and neurite outgrowth, while A550T/T567A mutants showed impaired nerve terminal targeting.

Conclusions:

• SYN1 is a novel predisposing gene for autism spectrum disorders (ASDs) and epilepsy.
• SYN1 mutations disrupt synaptic homeostasis, supporting its role in the pathogenesis of both ASDs and epilepsy.
• Functional studies confirm the detrimental impact of identified SYN1 mutations on neuronal function.