Journal article
A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2
Journal of Biological Chemistry, Vol.287(34), pp.28986-29002
2012
Abstract
Hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, producing hypertonia and apnea episodes. Although rare, this orphan disorder can have serious consequences, including sudden infant death. Dominant and recessive mutations in the human glycine receptor (GlyR) α1 gene (GLRA1) are the major cause of this disorder. However, recessive mutations in the presynaptic Na+/Cl--dependent glycine transporter GlyT2 gene (SLC6A5) are rapidly emerging as a second major cause of startle disease. In this study, systematic DNA sequencing of SLC6A5 revealed a new dominant GlyT2 mutation: pY705C (c.2114A→G) in transmembrane domain 11, in eight individuals from Spain and the United Kingdom. Curiously, individuals harboring this mutation show significant variation in clinical presentation. In addition to classical hyperekplexia symptoms, some individuals had abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability. We functionally characterized this mutation using molecular modeling, electrophysiology, [3H]glycine transport, cell surface expression, and cysteine labeling assays. We found that the introduced cysteine interacts with the cysteine pair Cys-311-Cys-320 in the second external loop of GlyT2. This interaction impairs transporter maturation through the secretory pathway, reduces surface expression, and inhibits transport function. Additionally, Y705C presents altered H+ and Zn2+ dependence of glycine transport that may affect the function of glycinergic neurotransmission in vivo. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Details
- Title
- A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2
- Authors
- C Giménez (Author) - Universidad Autónoma de Madrid, SpainG Pérez-Siles (Author) - Universidad Autónoma de Madrid, SpainJ Martínez-Villarreal (Author) - Universidad Autónoma de Madrid, SpainE Arribas-González (Author) - Universidad Autónoma de Madrid, SpainE Jiménez (Author) - Universidad Autónoma de Madrid, SpainE Núñe (Author) - Universidad Autónoma de Madrid, SpainJ De Juan-Sanz (Author) - Universidad Autónoma de Madrid, SpainE Fernández-Sánchez (Author) - Universidad Autónoma de Madrid, SpainN García-Tardón (Author) - Universidad Autónoma de Madrid, SpainI Ibáñez (Author) - Universidad Autónoma de Madrid, SpainV Romanelli (Author) - Instituto de Salud Carlos III, SpainJ Nevado (Author) - Instituto de Salud Carlos III, SpainV M James (Author) - University college London, United KingdomM Topf (Author) - Birkbeck College, United KingdomS K Chung (Author) - Swansea University, United KingdomR H Thomas (Author) - Swansea University, United KingdomL R Desviat (Author) - Universidad Autónoma de Madrid, SpainC Aragón (Author) - Universidad Autónoma de Madrid, SpainF Zafra (Author) - Universidad Autónoma de Madrid, SpainM I Rees (Author) - Swansea University, United KingdomP Lapunzina (Author) - Instituto de Salud Carlos III, SpainRobert J Harvey (Author) - University college London, United KingdomB López-Corcuera (Author) - Universidad Autónoma de Madrid, Spain
- Publication details
- Journal of Biological Chemistry, Vol.287(34), pp.28986-29002
- Publisher
- American Society for Biochemistry and Molecular Biology, Inc.
- Date published
- 2012
- DOI
- 10.1074/jbc.M111.319244
- ISSN
- 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
- 99451272302621
- Output Type
- Journal article
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