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

Rees, M.I., Harvey, K., Pearce, B.R., Chung, S-K., Duguid, I.C., Thomas, P., Beatty, S., Graham, G.E., Armstrong, L., Shiang, R., Abbott, K.J., Zuberi, S.M., Stephenson, J.B.P., Owen, M.J., Tijssen, M.A.J., van den Maagdenberg, A.M.J.M., Smart, T.G., Supplisson, S. and Harvey, R.J. (2006) Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nature Genetics, 38 (7). pp. 801-806. 10.1038/ng1814.

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DOI: 10.1038/ng1814

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) 1 subunit (GLRA1)1, 2, 3. Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR subunit (GLRB)4, gephyrin (GPHN)5 and RhoGEF collybistin (ARHGEF9)6. However, many individuals diagnosed with sporadic hyperekplexia do not carry mutations in these genes2, 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.

Item Type:Article
Departments, units and centres:Department of Pharmacology > Department of Pharmacology
ID Code:2155
Journal or Publication Title:Nature Genetics
Deposited By:Library Staff
Deposited On:09 Jun 2011 15:48
Last Modified:10 Nov 2011 09:44

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