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

Mark I Rees^1, 3, 14, Kirsten Harvey^2, 14, Brian R Pearce², Seo-Kyung Chung^1, 3, Ian C Duguid⁴, Philip Thomas⁴, Sarah Beatty³, Gail E Graham⁵, Linlea Armstrong⁶, Rita Shiang⁷, Kim J Abbott⁸, Sameer M Zuberi⁹, John B P Stephenson⁹, Michael J Owen¹⁰, Marina A J Tijssen¹¹, Arn M J M van den Maagdenberg¹², Trevor G Smart⁴, Stéphane Supplisson¹³ & Robert J Harvey²

¹  School of Medicine, University of Wales Swansea, Singleton Park, West Glamorgan SA2 8PP, UK.

²  Department of Pharmacology, The School of Pharmacy, 29–39 Brunswick Square, London WC1N 1AX, UK.

³  Department of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland, New Zealand.

⁴  Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

⁵  Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ontario K1H 8L1, Canada.

⁶  Department of Medical Genetics, Children's and Women's Health Centre of British Columbia, 4500 Oak Street, Vancouver, British Columbia V6H 3N1, Canada.

⁷  Department of Human Genetics, Virginia Commonwealth University Medical Center, P.O. Box 980033, Richmond, Virginia 23298-0033, USA.

⁸  Women's and Children's Hospital, 72 King William Road, Adelaide, South Australia, Australia.

⁹  Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, G3 8SJ, UK.

¹⁰  Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK.

¹¹  Department of Neurology, Academic Medical Centre, University of Amsterdam, PO BOX 22660, 1100 DD Amsterdam, The Netherlands.

¹²  Department of Neurology and Department of Human Genetics, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands.

¹³  Laboratoire de Neurobiologie, CNRS UMR8544, Ecole Normale Supérieure, 46 Rue d'Ulm, 75005 Paris, France.

¹⁴  These authors contributed equally to this work.

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 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.

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