title: Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease.
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) alpha1 subunit (GLRA1). Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR beta subunit (GLRB), gephyrin (GPHN) and RhoGEF collybistin (ARHGEF9). However, many individuals diagnosed with sporadic hyperekplexia do not carry mutations in these genes. 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.
authors.affiliation: School of Medicine, University of Wales Swansea, Singleton Park, West Glamorgan SA2 8PP, UK. m.i.rees@swansea.ac.uk
authors.forename: Mark I
authors.initials: MI
authors.lastname: Rees
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harvey
authors.forename: Brian R
authors.initials: BR
authors.lastname: Pearce
authors.forename: Seo-Kyung
authors.initials: SK
authors.lastname: Chung
authors.forename: Ian C
authors.initials: IC
authors.lastname: Duguid
authors.forename: Philip
authors.initials: P
authors.lastname: Thomas
authors.forename: Sarah
authors.initials: S
authors.lastname: Beatty
authors.forename: Gail E
authors.initials: GE
authors.lastname: Graham
authors.forename: Linlea
authors.initials: L
authors.lastname: Armstrong
authors.forename: Rita
authors.initials: R
authors.lastname: Shiang
authors.forename: Kim J
authors.initials: KJ
authors.lastname: Abbott
authors.forename: Sameer M
authors.initials: SM
authors.lastname: Zuberi
authors.forename: John B P
authors.initials: JB
authors.lastname: Stephenson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Marina A J
authors.initials: MA
authors.lastname: Tijssen
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
authors.forename: Stéphane
authors.initials: S
authors.lastname: Supplisson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harvey
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D005260:Female; D050487:Glycine Plasma Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D017729:Presynaptic Terminals / Q000502:physiology; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013216:Reflex, Startle / Q000235:genetics* / Q000502:physiology; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D050487:Glycine Plasma Membrane Transport Proteins; D011993:Recombinant Fusion Proteins; C493271:SLC6A5 protein, human