title: Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia.
abstract: Hyperekplexia is a rare, but potentially fatal, neuromotor disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden, unexpected auditory or tactile stimuli. This disorder is primarily caused by inherited mutations in the genes encoding the glycine receptor (GlyR) alpha1 subunit (GLRA1) and the presynaptic glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of GLRA1 in 88 new unrelated human hyperekplexia patients revealed 19 sequence variants in 30 index cases, of which 21 cases were inherited in recessive or compound heterozygote modes. This indicates that recessive hyperekplexia is far more prevalent than previous estimates. From the 19 GLRA1 sequence variants, we have investigated the functional effects of 11 novel and 2 recurrent mutations. The expression levels and functional properties of these hyperekplexia mutants were analyzed using a high-content imaging system and patch-clamp electrophysiology. When expressed in HEK293 cells, either as homomeric alpha1 or heteromeric alpha1beta GlyRs, subcellular localization defects were the major mechanism underlying recessive mutations. However, mutants without trafficking defects typically showed alterations in the glycine sensitivity suggestive of disrupted receptor function. This study also reports the first hyperekplexia mutation associated with a GlyR leak conductance, suggesting tonic channel opening as a new mechanism in neuronal ligand-gated ion channels.
authors.affiliation: Institute of Life Science, School of Medicine, Swansea University, Swansea, United Kingdom.
authors.forename: Seo-Kyung
authors.initials: SK
authors.lastname: Chung
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Vanbellinghen
authors.forename: Jonathan G L
authors.initials: JG
authors.lastname: Mullins
authors.forename: Angela
authors.initials: A
authors.lastname: Robinson
authors.forename: Janina
authors.initials: J
authors.lastname: Hantke
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Hammond
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gilbert
authors.forename: Michael
authors.initials: M
authors.lastname: Freilinger
authors.forename: Monique
authors.initials: M
authors.lastname: Ryan
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kruer
authors.forename: Amira
authors.initials: A
authors.lastname: Masri
authors.forename: Candan
authors.initials: C
authors.lastname: Gurses
authors.forename: Colin
authors.initials: C
authors.lastname: Ferrie
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harvey
authors.forename: Rita
authors.initials: R
authors.lastname: Shiang
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.forename: Frederick
authors.initials: F
authors.lastname: Andermann
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
authors.forename: Rhys H
authors.initials: RH
authors.lastname: Thomas
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harvey
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lynch
authors.forename: Mark I
authors.initials: MI
authors.lastname: Rees
mesh_terms: D002460:Cell Line; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D009122:Muscle Hypertonia / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D018009:Receptors, Glycine / Q000235:genetics*; D012021:Reflex, Abnormal / Q000235:genetics*; D013216:Reflex, Startle / Q000235:genetics*; D014162:Transfection
chemical_list: C000657604:GLRA1 protein, human; D018009:Receptors, Glycine