Dominant and recessive mutations have been identified in GLRA1 gene as pathogenic variants in many individuals with the familial form of Hyperekplexia and occasionally in simplex cases.
Our findings contribute to a growing list GLRA1 mutations associated with hyperekplexia and provide new insights into correlations between phenotype and GLRA1 mutations.
However, we consider this unlikely as the depleted chloride gradient should also lead to pain sensitization and to a hyperekplexia phenotype that correlates with mutation severity, neither of which is observed in patients with GLRA1hyperekplexia mutations.
The clinical diagnosis was subsequently revised to hyperekplexia and confirmed by mutation analysis of the GLRA1 gene, which showed c.497G>C (p.Cys166Ser) and c.526delG (p.Asp176Metfs*16).Both of them are novel mutations.
The infant showed a marked improvement of the startle response and muscle hypertonia with clonazepam which is a strong clinical feature of GLRA1-mediated hyperekplexia.[Published with video sequences].
The postsynaptic α(1)-subunit (GLRA1) of the inhibitory glycine receptor (GlyR) and the cognate presynaptic glycine transporter (SLC6A5/GlyT2) are well-established genes of effect in hyperekplexia.
In conclusion, a novel p.W170S mutation in the extracellular ligand binding domain of glycine receptor α1 subunit was detected in patients with hyperekplexia and mild mental retardation.
The mutations in the glycine receptor α1 subunit (α1R271Q/L) which cause the neuromotor disorder hyperekplexia are on example of such allosteric mutations.In this issue of the BJP, Shan et al. show that normal function was restored to these mutant receptors by substitution of the segment which contained the mutated position, by a homologous one.
The primary cause of startle disease is defective inhibitory glycinergic transmission due to mutations in the postsynaptic glycine receptor (GlyR) α1 subunit gene (GLRA1).
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.
We describe a hyperekplexia family carrying the novel dominant missense allele GLRA1(S267N), that affects agonist responses and ethanol modulation of the mutant receptor.
Thus, the hyperekplexia phenotype of Glra1(D80A) mice is due to the loss of Zn(2+) potentiation of alpha1 subunit containing GlyRs, indicating that synaptic Zn(2+) is essential for proper in vivo functioning of glycinergic neurotransmission.
Here, we report five new pedigrees of recessive hyperekplexia in apparently unrelated families of Kurdish origin associated with a deletion of exons 1-7 of the GLRA1 gene.
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).