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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) α1 subunit (GLRA1)1,2,3. Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR β 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.

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Acknowledgements

We thank E.A. Peeters and K. Braun for referrals of research participants. This work was supported by grants from the Medical Research Council (UK) to R.J.H. and T.G.S., from the Neurological Foundation for New Zealand and Auckland Medical Research Foundation to M.I.R. and from the Fédération pour la Recherche sur le Cerveau and the Association Française contre les Myopathies to S.S.

Author information

Author notes

    • Mark I Rees
    •  & Kirsten Harvey

    These authors contributed equally to this work.

Affiliations

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

    • Mark I Rees
    •  & Seo-Kyung Chung
  2. Department of Pharmacology, The School of Pharmacy, 29–39 Brunswick Square, London WC1N 1AX, UK.

    • Kirsten Harvey
    • , Brian R Pearce
    •  & Robert J Harvey
  3. Department of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland, New Zealand.

    • Mark I Rees
    • , Seo-Kyung Chung
    •  & Sarah Beatty
  4. Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

    • Ian C Duguid
    • , Philip Thomas
    •  & Trevor G Smart
  5. Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ontario K1H 8L1, Canada.

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

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

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

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

    • Sameer M Zuberi
    •  & John B P Stephenson
  10. Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK.

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

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

    • Arn M J M van den Maagdenberg
  13. Laboratoire de Neurobiologie, CNRS UMR8544, Ecole Normale Supérieure, 46 Rue d'Ulm, 75005 Paris, France.

    • Stéphane Supplisson

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The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mark I Rees or Robert J Harvey.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Sequencing panel representing the pathological hyperekplexia variants detected in SLC6A5

  2. 2.

    Supplementary Fig. 2

    Electrophysiological analysis of GlyT2 mutants in NG108-15 cells

  3. 3.

    Supplementary Table 1

    Oligonucleotide primers for analysis of the human GlyT2 gene (SLC6A5) and amplification of human GlyT2 cDNAs

  4. 4.

    Supplementary Table 2

    Patient/mutation detection rates in hyperekplexia candidate genes

  5. 5.

    Supplementary Table 3

    Single nucleotide polymorphisms detected in the coding regions of the human GlyT2 gene (SLC6A5)

  6. 6.

    Supplementary Note

    Detailed clinical reports for affected SLC6A5 patients and relatives

Videos

  1. 1.

    Supplementary Video 1

    Patient 6 Video. When placed in water for his bath, he developed rapid quivering of his limbs, with a staccato grunting cry, followed by silence and intense stiffening in a semi-flexed posture. He became deeply cyanosed and had anoxic non-epileptic seizures in the form of spasms, together with forcible urination. Thereafter he had a grey moribund appearance. When an episode was induced with EEG and ECG leads attached, EMG “spikes” appeared on EEG channels overlying muscle and on the ECG channel, either as repetitive giant potentials in the “clonic” phase or as closely spaced giant muscle potentials in the “tonic” phase. Meanwhile the EEG became isoelectric, and the ECG showed junctional bradycardia, reflecting severe syncope.

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DOI

https://doi.org/10.1038/ng1814

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