We investigated the molecular basis of hyperekplexia (STHE), an inherited neurological disorder characterised by neonatal hypertonia and an exaggerated startle response, in a kindred and identified a novel missense mutation in the pore-lining M2 domain of the alpha1 subunit of the glycine receptor (GLRA1).
The primary cause of startle disease is defective inhibitory glycinergic transmission due to mutations in the postsynaptic glycine receptor (GlyR) α1 subunit gene (GLRA1).
However, recessive transmission is seen in the mouse mutant spasmodic which resembles startle disease phenotypically and is also associated with mutations in Glra 1.
Based on the identical phenotypes of mouse lines carrying mutant alleles of the alpha 1 and beta subunit genes, GLRB was assumed to be a candidate gene for those cases of hyperekplexia that cannot be associated with mutations of 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.
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.
The previously identified hyperekplexia mutation GLRA1(P250T), located within the intracellular TM1-2 loop of the GlyR alpha1 subunit, results in altered receptor activation and desensitization.
Hyperekplexia (HE), or startle disease, is usually a familial disorder associated with mutations in the glycine receptor alpha1 subunit gene (GLRA1), characterised by exaggerated startle reactions to unexpected auditory, somaesthetic and visual stimuli.
The disease caused by mutation in GLRB in mice supports the notion that human hyperekplexia with no detectable mutations in GLRA1 may harbor mutations in GLRB.
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).
Thus, only clinically typical hyperekplexia appears to be consistently associated with GLRA1 mutations, and these affect a specific extracellular domain of the protein.
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.
Different from the dominant trait of clinical hyperekplexia associated with GLRA1 (P250T), wildtype subunits dominated the functional properties of mixed receptor complexes in the recombinant system.
However, new research suggests that mutations in the gene encoding the presynaptic glycine transporter GlyT2 are a second major cause of human hyperekplexia, as well as congenital muscular dystonia type 2 (CMD2) in cattle.
Providing a better understanding of the molecular regulation of GlyT2 may help future investigations into the molecular basis of human disease states caused by dysfunctional glycinergic neurotransmission, such as hyperekplexia and chronic pain.
However, recessive mutations in the presynaptic Na(+)/Cl(-)-dependent glycine transporter GlyT2 gene (SLC6A5) are rapidly emerging as a second major cause of startle disease.