Hyperekplexia

The first gene linked conclusively to hyperekplexia was GLRA1.[6] The GLRA1 gene encodes the glycine receptor, alpha 1 subunit, which, together with the glycine receptor beta subunit, forms synaptic glycine receptors. Inhibitory glycine receptors are ligand-gated chloride channels that facilitate fast responses in the brainstem and spinal-cord. Homomeric glycine receptors composed exclusively of alpha-1 subunits exhibit normal ion channel electrophysiology, but are not sequestered at the synaptic junction.[7] Wild-type glycine receptors are thus presumed to be pentameric heteromers of the alpha-1 and beta subunits, in either a 3:2 or 2:3 ratio.[7]

Within these heteromers, it is believed that the alpha-1 subunits bind glycine and undergo a conformational change, inducing a conformational change in the pentamer, causing the ion-channel to open. Although autosomal dominant[6] inheritance was initially reported, there are at least as many cases described with autosomal recessive inheritance.[8] Thus far, the general rule is that mutations causing structurally normal proteins that cannot bind glycine or cannot properly undergo a required conformational change in response to glycine will result in a dominant form of the disease, while mutations that result in truncated or greatly malformed subunits that cannot be integrated into a receptor protein will result in a recessive form.[8]

The GLRB gene encodes the beta subunit of the glycine receptor. Homomeric glycine receptors composed of beta subunits do not open in response to glycine stimulation,[9] however, the beta subunit is essential for proper receptor localization, through its interactions with gephyrin, which results in receptor clustering at the synaptic cleft.[10] As such, the defects within the GLRB gene show autosomal recessive inheritance.[11]

The SLC6A5 gene encodes the GlyT2 transporter, a neuronal pre-synaptic glycine re-uptake transporter. In comparison to the GlyT1 transporter, found mostly in glial cells, GlyT2 helps maintain a high concentration of glycine within the axon terminal of glycinergic neurons.[12] Mutations of the SLC6A5 gene have been associated with hyperekplexia in an autosomal recessive inheritance pattern.[13] Defects within this gene are hypothesized either to affect the incorporation of the transporter into the cellular membrane or to affect its affinity for the molecules it transports: sodium ions, chloride ions and glycine.[13] Any of these actions would drastically reduce the pre-synaptic cell's ability to produce the high vesicular concentrations of glycine necessary for proper glycine neurotransmission. GPHN and ARHGEF9 are often included in lists of genetic causes of hyperekplexia - but, in fact, they produce a much more complex phenotype, very distinct from classical hyperekplexia. As such they are no longer considered to be causative genes.

Gephyrin, an integral membrane protein believed to coordinate glycine receptors, is coded by the gene GPHN. A heterozygous mutation in this gene has been identified in one sporadic case of hyperekplexia, though experimental data is inconclusive as to whether the mutation itself is, in fact, pathogenic.[14] Gephyrin is essential for glycine receptor clustering at synaptic junctions, through its action of binding both the glycine receptor beta subunit and internal cellular microtubule structures.[10] Gephyrin also assists in clustering GABA receptors at synapses and molybdenum cofactor synthesis.[15] Because of gephyrin's multi-functional nature, in mutated form it is not presumed to be a common genetic source of hyperekplexia.[14]

A defect within the gene coding for collybistin, ARHGEF9, has been shown to cause hyperekplexia occurring with epilepsy.[16] Since the ARHGEF9 gene is on the X chromosome, this gene displays X-linked recessive heritance. The collybistin protein is responsible for proper gephyrin targeting, which is crucial for the proper localization of glycine and GABA receptors. Deficiencies in collybistin function would result in a lack of glycine and GABA receptors at the synaptic cleft.[16]