Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in hyperekplexia.
The alpha(1)-inhibitory glycine receptor is a ligand-gated chloride channel composed of three ligand-binding alpha1-subunits and two structural beta-subunits that are clustered on the postsynaptic membrane of inhibitory glycinergic neurons. Dominant and recessive mutations in GLRA1 subunits have been associated with a proportion of individuals and families with startle disease or hyperekplexia (MIM: 149400). Following SSCP and bi-directional di-deoxy fingerprinting mutational analysis of 22 unrelated individuals with hyperekplexia and hyperekplexia-related conditions, we report further novel missense mutations and the first nonsense point mutations in GLRA1, the majority of which localise outside the regions previously associated with dominant, disease-segregating mutations. Population studies reveal the unique association of each mutation with disease, and reveals that a proportion of sporadic hyperekplexia is accounted for by the homozygous inheritance of recessive GLRA1 mutations or as part of a compound heterozygote.
Rees
M I
MI
Department of Molecular Medicine, University of Auckland Medical School, Postbag 92019, Auckland, New Zealand. m.rees@auckland.ac.nz
Lewis
T M
TM
Vafa
B
B
Ferrie
C
C
Corry
P
P
Muntoni
F
F
Jungbluth
H
H
Stephenson
J B
JB
Kerr
M
M
Snell
R G
RG
Schofield
P R
PR
Owen
M J
MJ
D000595:Amino Acid Sequence; D001483:Base Sequence; D018389:Codon, Nonsense; D016172:DNA Fingerprinting; D018076:DNA, Complementary / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D009122:Muscle Hypertonia / Q000235:genetics*; D020125:Mutation, Missense; D018807:Polymorphism, Single-Stranded Conformational; D018009:Receptors, Glycine / Q000235:genetics*; D012021:Reflex, Abnormal / Q000235:genetics*; D013216:Reflex, Startle / Q000235:genetics*
D018389:Codon, Nonsense; D018076:DNA, Complementary; C000657604:GLRA1 protein, human; D018009:Receptors, Glycine