Trends in Genetics
ReviewThe genetics of hyperekplexia: more than startle!
Section snippets
Inhibitory glycinergic synapses in health and disease
Hyperekplexia or startle disease (OMIM: 149400; see Glossary) is caused by defects in mammalian glycinergic neurotransmission, resulting in a complex motor disorder characterised by neonatal hypertonia and an exaggerated startle reflex. This disorder affects newborn children and is characterised by noise or touch-induced non-epileptic seizures that result in muscle stiffness and apnea (suspension of breathing). Although rare, this disorder can have serious consequences, including brain damage
Postsynaptic causes of hyperekplexia: mutations in glycine receptor subunit genes and associated clustering proteins
Inhibitory glycine receptors (GlyRs) are heteropentameric ligand-gated chloride ion channels that facilitate fast-response, inhibitory neurotransmission in the human brainstem and spinal cord. Missense, nonsense and frameshift mutations in the GlyR α1 subunit gene (GLRA1) on chromosome 5q33.1 represent the primary cause of hyperekplexia 4, 5, 6, although large deletions in GLRA1 have also been described in patients of Turkish and Arabian ancestry 7, 8 (Figure 1a; Supplementary Table S1). The
The involvement of the glycine transporter glycine transporter 2 in hyperekplexia
Glycine transporters (GlyTs) are key members of the Na+/Cl−-dependent transporter superfamily 21, 22, 23, which includes transporters for GABA, biogenic amines (norepinephrine, dopamine, serotonin, proline), osmolytes (betaine, taurine and creatine) and several ‘orphan’ amino acid transporters [23] that are still undergoing functional analysis. By contrast, GlyTs are well characterised; they perform dual functions at both inhibitory glycinergic and excitatory glutamatergic synapses, resulting
Additional presynaptic candidates for genetic screening in hyperekplexia
The discovery that hyperekplexia can have presynaptic and postsynaptic causes of disease has revealed further candidates for genetic screening in hyperekplexia, including the vesicular inhibitory amino acid transporter (VIAAT) [34] and the GlyT2 interacting proteins syntenin-1 [35] and unc-33 like phosphoprotein 6 (ULIP6) [36]. VIAAT is a mammalian homolog of the UNC-47 protein, responsible for the ‘uncoordinated’ Caenorhabditis elegans mutant unc-47, known to be defective in presynaptic GABA
A GlyT2 defect in congenital muscular dystonia type 2 in cattle
Because mutations in the human GlyT2 gene are now a recognized cause of human hyperekplexia 31, 33, we conducted a retrospective analysis of unresolved animal disorders in which a glycinergic deficit was implicated and found examples in dogs [43], horses [44] and cattle [45]. Interestingly, these disorders are often labelled as ‘congenital myoclonus’ (i.e. sudden contraction of a group of muscle cells followed by immediate relaxation). However, these disorders might more accurately be described
Analogies with childhood idiopathic generalised epilepsies
The discovery of presynaptic and postsynaptic deficits in glycinergic synapses might also have applications in the study of other neurological disorders in which defects in postsynaptic receptors have been identified. For example, mutations in inhibitory GABAA receptor subunit genes are associated with rare familial forms of idiopathic generalised epilepsy 50, 51, such as childhood absence epilepsy (CAE), generalised epilepsy with generalised seizures plus (GEFS+) and juvenile myoclonic
Concluding remarks and future perspectives
The identification of mutations in the human glycine transporter 2 (GlyT2) gene 31, 33 has revealed a second major cause of hyperekplexia, and provided a rich resource for future structural, biochemical and electrophysiological analyses of neurotransmitter transporter function. In addition, many patients and families affected by hyperekplexia have now been provided with an unequivocal explanation for their condition and can receive genetic counselling. Future genetic research will focus on
Acknowledgements
Research in our laboratories is supported by grants from the Medical Research Council (G0500833 to R.J.H., G0501258 to K.H. and G0601585 to R.J.H., K.H. and M.I.R.) and the Wales Office of Research and Development (Wales Epilepsy Research Network to M.I.R.). M.T. is funded by a MRC Career Development Award (G0600084).
Glossary
- GABAA receptors (GABAARs)
- inhibitory receptors for the neurotransmitter γ-aminobutyric acid (GABA), composed of pentameric assemblies of a diverse range of subunits (α1–6, β1–3, γ1–3, δ, ɛ, θ and π). Mutations in the genes for the GABAAR α1, γ2 and δ subunits (GABRA1, GABRG2 and GABRD) have been implicated in certain idiopathic generalised epilepsies.
- Glycine receptors (GlyRs)
- inhibitory receptors for the amino acid glycine, composed of pentameric assemblies of α (α1-α4) and β subunits. Mutations
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