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Nat Genet. 2006 Jul;38(7):801-6. Epub 2006 Jun 4.

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

Author information

1
School of Medicine, University of Wales Swansea, Singleton Park, West Glamorgan SA2 8PP, UK. m.i.rees@swansea.ac.uk

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) alpha1 subunit (GLRA1). Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR beta subunit (GLRB), gephyrin (GPHN) and RhoGEF collybistin (ARHGEF9). However, many individuals diagnosed with sporadic hyperekplexia do not carry mutations in these genes. 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.

PMID:
16751771
PMCID:
PMC3204411
DOI:
10.1038/ng1814
[Indexed for MEDLINE]
Free PMC Article
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