Journal article
Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease
Journal of Biological Chemistry, Vol.287(34), pp.28975-28985
2012
Abstract
Hereditary hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, leading to hypertonia and apnea episodes. Missense, nonsense, frameshift, splice site mutations, and large deletions in the human glycine receptor α1 subunit gene (GLRA1) are the major known cause of this disorder. However, mutations are also found in the genes encoding the glycine receptor β subunit (GLRB) and the presynaptic Na+/Cl--dependent glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of SLC6A5 in 93 new unrelated human hyperekplexia patients revealed 20 sequence variants in 17 index cases presenting with homozygous or compound heterozygous recessive inheritance. Five apparently unrelated cases had the truncating mutation R439X. Genotype-phenotype analysis revealed a high rate of neonatal apneas and learning difficulties associated with SLC6A5 mutations. From the 20 SLC6A5 sequence variants, we investigated glycine uptake for 16 novel mutations, confirming that all were defective in glycine transport. Although the most common mechanism of disrupting GlyT2 function is protein truncation, new pathogenic mechanisms included splice site mutations and missense mutations affecting residues implicated in Cl- binding, conformational changes mediated by extracellular loop 4, and cation-π interactions. Detailed electrophysiology of mutation A275T revealed that this substitution results in a voltage-sensitive decrease in glycine transport caused by lower Na+ affinity. This study firmly establishes the combination of missense, nonsense, frameshift, and splice site mutations in the GlyT2 gene as the second major cause of startle disease. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Details
- Title
- Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease
- Authors
- E Carta (Author) - University College London, United KingdomS K Chung (Author) - Swansea University, United KingdomV M James (Author) - University College London, United KingdomA Robinson (Author) - Swansea University, United KingdomJ L Gill (Author) - University College London, United KingdomN Remy (Author) - Liège University Hospital, BelgiumJ F Vanbellinghen (Author) - Institut de Pathologie et de Génétique, BelgiumC J G Drew (Author) - Swansea University, United KingdomS Cagdas (Author) - Poma Hospital, ItalyD Cameron (Author) - Glan Clwyd Hospital, United KingdomF M Cowan (Author) - Imperial College, United KingdomM Del Toro (Author) - Hospital General Universitari Vall d'Hebron, SpainG E Graham (Author) - Children's Hospital of Eastern Ontario, CanadaA Y Manzur (Author) - Great Ormond Street Hospital for Children, United KingdomA Masri (Author) - University of Jordan, JordanS Rivera (Author) - Centre Hospitalier de la Côte Basque, FranceE Scalais (Author) - Centre Hospitalier de Luxembourg, LuxembourgR Shiang (Author) - Virginia Commonwealth University, United StatesK Sinclair (Author) - Royal Children's HospitalC A Stuart (Author) - Cumberland Infirmary, United KingdomM A J Tijssen (Author) - University Medical Centre Groningen, NetherlandG Wise (Author) - Sydney Children's HospitalS M Zuberi (Author) - Royal Hospital for Sick Children, United KingdomK Harvey (Author) - University College London, United KingdomB R Pearce (Author) - University College London, United KingdomM Topf (Author) - Institute of Structural and Molecular Biology, United KingdomR H Thomas (Author) - Swansea University, United KingdomS Supplisson (Author) - Institut de Biologie de l'Ecole Normale Supérieure, FranceM I Rees (Author) - Swansea University, United KingdomRobert J Harvey (Author) - University College London, United Kingdom
- Publication details
- Journal of Biological Chemistry, Vol.287(34), pp.28975-28985
- Publisher
- American Society for Biochemistry and Molecular Biology, Inc.
- Date published
- 2012
- DOI
- 10.1074/jbc.M112.372094
- ISSN
- 0021-9258; 0021-9258
- Copyright note
- Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc. The published version is reproduced here in accordance with the publisher's copyright policy.
- Organisation Unit
- School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99450803902621
- Output Type
- Journal article
- Research Statement
- false
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