Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia.
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.
Chung
Seo-Kyung
SK
Institute of Life Science, School of Medicine, Swansea University, Swansea, United Kingdom.
Vanbellinghen
Jean-François
JF
Mullins
Jonathan G L
JG
Robinson
Angela
A
Hantke
Janina
J
Hammond
Carrie L
CL
Gilbert
Daniel F
DF
Freilinger
Michael
M
Ryan
Monique
M
Kruer
Michael C
MC
Masri
Amira
A
Gurses
Candan
C
Ferrie
Colin
C
Harvey
Kirsten
K
Shiang
Rita
R
Christodoulou
John
J
Andermann
Frederick
F
Andermann
Eva
E
Thomas
Rhys H
RH
Harvey
Robert J
RJ
Lynch
Joseph W
JW
Rees
Mark I
MI
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
C000657604:GLRA1 protein, human; D018009:Receptors, Glycine