Abstract
Hereditary hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, leading to hypertonia and apnea episodes. Missense, nonsense, frameshift, splice site mutations, and large deletions in the human glycine receptor α1 subunit gene (GLRA1) are the major known cause of this disorder. However, mutations are also found in the genes encoding the glycine receptor β subunit (GLRB) and the presynaptic Na(+)/Cl(-)-dependent glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of SLC6A5 in 93 new unrelated human hyperekplexia patients revealed 20 sequence variants in 17 index cases presenting with homozygous or compound heterozygous recessive inheritance. Five apparently unrelated cases had the truncating mutation R439X. Genotype-phenotype analysis revealed a high rate of neonatal apneas and learning difficulties associated with SLC6A5 mutations. From the 20 SLC6A5 sequence variants, we investigated glycine uptake for 16 novel mutations, confirming that all were defective in glycine transport. Although the most common mechanism of disrupting GlyT2 function is protein truncation, new pathogenic mechanisms included splice site mutations and missense mutations affecting residues implicated in Cl(-) binding, conformational changes mediated by extracellular loop 4, and cation-π interactions. Detailed electrophysiology of mutation A275T revealed that this substitution results in a voltage-sensitive decrease in glycine transport caused by lower Na(+) affinity. This study firmly establishes the combination of missense, nonsense, frameshift, and splice site mutations in the GlyT2 gene as the second major cause of startle disease.
Highlights
Hereditary startle disease is caused by genetic defects in inhibitory glycine receptor and transporter genes
Hereditary hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, leading to hypertonia and apnea episodes
Mutations are found in the genes encoding the glycine receptor  subunit (GLRB) and the presynaptic Na؉/Cl؊-dependent glycine transporter GlyT2 (SLC6A5)
Summary
Recessive mutations in SLC6A5 represent a second major cause of startle disease. Significance: Genetic screening for startle disease should encompass both presynaptic and postsynaptic causes of disease. Nonsense, frameshift, splice site mutations, and large deletions in the human glycine receptor ␣1 subunit gene (GLRA1) are the major known cause of this disorder. The major known genetic cause of hyperekplexia is missense, nonsense, frameshift, or splice site mutations in the glycine receptor (GlyR)4 ␣1 gene (GLRA1) (8 –10), large GLRA1 deletions are common in patients of Kurdish descent [11, 12]. Because many patients do not harbor defects in these genes, some years ago we began to consider hyperekplexia as a synaptopathy This led to the identification of missense, nonsense, and frameshift mutations in the GlyT2 gene (SLC6A5), encoding a Naϩ/ClϪ-dependent neurotransmitter transporter that maintains a high presynaptic pool of glycine at glycinergic synapses [17, 18]. Taken together with our recent study on GLRA1 mutations in startle disease [10], these results suggest that recessive modes of inheritance are far more common on a population basis than dominant mutations, explaining the apparent sporadic nature of this rare disorder
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