Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease

Abstract

Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) α1 subunit (GLRA1)^1,2,3. Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR β subunit (GLRB)⁴, gephyrin (GPHN)⁵ and RhoGEF collybistin (ARHGEF9)⁶. However, many individuals diagnosed with sporadic hyperekplexia do not carry mutations in these genes^2,3,4,5,6,7. Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia. Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na⁺ binding sites.