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Gene Review

GLRA1  -  glycine receptor, alpha 1

Homo sapiens

Synonyms: Glycine receptor 48 kDa subunit, Glycine receptor strychnine-binding subunit, Glycine receptor subunit alpha-1, HKPX1, STHE
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Disease relevance of GLRA1

  • Hereditary hyperekplexia, an autosomal dominant neurologic disorder characterized by an exaggerated startle reflex and neonatal hypertonia, can be caused by mutations in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor (GLRA1) [1].
  • In contrast, no GLRA1 transcripts were found in 10 nonmalignant nor 15 non-small-cell lung cancer biopsies [2].
  • Analysis of GLRA1 in hereditary and sporadic hyperekplexia: a novel mutation in a family cosegregating for hyperekplexia and spastic paraparesis [3].

Psychiatry related information on GLRA1

  • 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 [4].

High impact information on GLRA1

  • 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) [5].
  • In a recessive case of hyperekplexia, we found a deletion of exons 1-6 of the GLRA1 gene [6].
  • Dominant missense mutations in the human glycine receptor (GlyR) alpha 1 subunit gene (GLRA1) give rise to hereditary hyperekplexia [6].
  • In addition we describe an apparently sporadic case, the offspring of a consanguineous mating, who is homozygous for a novel mutation (T1112A) in GLRA 1, which results in the substitution of asparagine for isoleucine at position 244 of the mature protein [7].
  • In a pedigree showing dominant transmission of hyperekplexia, we identified a novel point mutation C1128A of GLRA1 [8].

Biological context of GLRA1

  • Here we describe the identification of point mutations in the gene encoding the alpha 1 subunit of the glycine receptor (GLRA1) in STHE patients from four different families [9].
  • Hyperekplexia phenotype due to compound heterozygosity for GLRA1 gene mutations [10].
  • Haplotype analysis using polymorphisms within and close to the GLRA1 locus suggests that this mutation has arisen at least twice (and possibly four times) [11].
  • Subsequently, mutations in the GLRA1 gene, encoding the alpha1 subunit of the glycine receptor, were found in hyperekplexia families with an autosomal dominant or recessive inheritance pattern [10].
  • Localization of the glycine receptor alpha 1 subunit gene (GLRA1) to chromosome 5q32 by FISH [12].

Anatomical context of GLRA1

  • Expression of GLRA1 in nontransformed cells is largely restricted to cells in the spinal cord, retina and brain stem [2].
  • The level of NRSF transcripts as well as the level of specifically bound NRSF to the NRSE correlated with the level of GLRA1 transcripts in SCLC cell lines [2].
  • Understanding of the molecular basis of paroxysmal disorders affecting the central nervous system has been revolutionalized with the identification of mutations in genes for the neurotransmitter receptors, GLRA1 and CHRNA4, and a voltage-gated potassium channel, KCNA1, as causes of inherited neurological disease [13].
  • Thus, we found no evidence to support a deficit in the cerebral cortex in patients with hereditary hyperekplexia due to mutations in the GLRA1 gene [14].
  • METHODS: Genomic DNA was extracted by standard procedures from peripheral blood leukocytes and exon 6 of the GLRA1 gene was amplified using primers and PCR conditions [15].

Associations of GLRA1 with chemical compounds

  • We previously reported two GLRA1 point mutations detected in 4 unrelated hyperekplexia families; both mutations were at nucleotide 1192 and resulted in the replacement of Arg271 by a glutamine (R271Q) in one case and a leucine (R271L) in the other [11].
  • Here, we describe a recessive point mutation (C1073G) in exon 7 of GLRA1 leading to an amino acid exchange of serine 231 to arginine in transmembrane region TM1 [16].
  • MoCo deficiency should be considered in the differential diagnosis of neonatal hyperekplexia, particularly in the instances of refractoriness to clonazepam, an early demise in infancy or the evidence of no mutations in the GLRA1 gene [17].

Other interactions of GLRA1

  • This neuromotor disorder is associated with mutations in the GlyR alpha1 and beta subunit genes (GLRA1 and GLRB) [18].
  • Hyperekplexia (MIM: 149400) is a neurological disorder characterized by an excessive startle response which can be caused by mutations in the alpha1-subunit (GLRA1) of the heteropentameric human inhibitory glycine receptor (hGlyR) [19].
  • Sequence analysis of 5'-flanking regions of glycine receptor (GlyR) subunit genes revealed a consensus motif for NRSE in the GLRA1 and GLRA3, but not in GLRB, genes [20].


  1. A missense mutation in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor in the spasmodic mouse. Ryan, S.G., Buckwalter, M.S., Lynch, J.W., Handford, C.A., Segura, L., Shiang, R., Wasmuth, J.J., Camper, S.A., Schofield, P., O'Connell, P. Nat. Genet. (1994) [Pubmed]
  2. Reduced expression of the neuron restrictive silencer factor permits transcription of glycine receptor alpha1 subunit in small-cell lung cancer cells. Gurrola-Diaz, C., Lacroix, J., Dihlmann, S., Becker, C.M., von Knebel Doeberitz, M. Oncogene (2003) [Pubmed]
  3. Analysis of GLRA1 in hereditary and sporadic hyperekplexia: a novel mutation in a family cosegregating for hyperekplexia and spastic paraparesis. Elmslie, F.V., Hutchings, S.M., Spencer, V., Curtis, A., Covanis, T., Gardiner, R.M., Rees, M. J. Med. Genet. (1996) [Pubmed]
  4. Frontal lobe dysfunction in sporadic hyperekplexia--case study and literature review. Gaitatzis, A., Kartsounis, L.D., Gacinovic, S., Costa, D.C., Harvey, K., Harvey, R.J., de Silva, R.N. J. Neurol. (2004) [Pubmed]
  5. Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Rees, M.I., Harvey, K., Pearce, B.R., Chung, S.K., Duguid, I.C., Thomas, P., Beatty, S., Graham, G.E., Armstrong, L., Shiang, R., Abbott, K.J., Zuberi, S.M., Stephenson, J.B., Owen, M.J., Tijssen, M.A., van den Maagdenberg, A.M., Smart, T.G., Supplisson, S., Harvey, R.J. Nat. Genet. (2006) [Pubmed]
  6. A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors. Brune, W., Weber, R.G., Saul, B., von Knebel Doeberitz, M., Grond-Ginsbach, C., Kellerman, K., Meinck, H.M., Becker, C.M. Am. J. Hum. Genet. (1996) [Pubmed]
  7. Evidence for recessive as well as dominant forms of startle disease (hyperekplexia) caused by mutations in the alpha 1 subunit of the inhibitory glycine receptor. Rees, M.I., Andrew, M., Jawad, S., Owen, M.J. Hum. Mol. Genet. (1994) [Pubmed]
  8. Novel GLRA1 missense mutation (P250T) in dominant hyperekplexia defines an intracellular determinant of glycine receptor channel gating. Saul, B., Kuner, T., Sobetzko, D., Brune, W., Hanefeld, F., Meinck, H.M., Becker, C.M. J. Neurosci. (1999) [Pubmed]
  9. Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Shiang, R., Ryan, S.G., Zhu, Y.Z., Hahn, A.F., O'Connell, P., Wasmuth, J.J. Nat. Genet. (1993) [Pubmed]
  10. Hyperekplexia phenotype due to compound heterozygosity for GLRA1 gene mutations. Vergouwe, M.N., Tijssen, M.A., Peters, A.C., Wielaard, R., Frants, R.R. Ann. Neurol. (1999) [Pubmed]
  11. Mutational analysis of familial and sporadic hyperekplexia. Shiang, R., Ryan, S.G., Zhu, Y.Z., Fielder, T.J., Allen, R.J., Fryer, A., Yamashita, S., O'Connell, P., Wasmuth, J.J. Ann. Neurol. (1995) [Pubmed]
  12. Localization of the glycine receptor alpha 1 subunit gene (GLRA1) to chromosome 5q32 by FISH. Baker, E., Sutherland, G.R., Schofield, P.R. Genomics (1994) [Pubmed]
  13. Genetics of the epilepsies. Elmslie, F., Gardiner, M. Curr. Opin. Neurol. (1995) [Pubmed]
  14. Magnetic resonance spectroscopy of cerebral cortex is normal in hereditary hyperekplexia due to mutations in the GLRA1 gene. Tijssen, M.A., Brown, P., MacManus, D., McLean, M.A., Davie, C. Mov. Disord. (2003) [Pubmed]
  15. Hyperekplexia (startle disease): a novel mutation (S270T) in the M2 domain of the GLRA1 gene and a molecular review of the disorder. Lapunzina, P., Sánchez, J.M., Cabrera, M., Moreno, A., Delicado, A., de Torres, M.L., Mori, A.M., Quero, J., Lopez Pajares, I. Mol. Diagn. (2003) [Pubmed]
  16. A novel recessive hyperekplexia allele GLRA1 (S231R): genotyping by MALDI-TOF mass spectrometry and functional characterisation as a determinant of cellular glycine receptor trafficking. Humeny, A., Bonk, T., Becker, K., Jafari-Boroujerdi, M., Stephani, U., Reuter, K., Becker, C.M. Eur. J. Hum. Genet. (2002) [Pubmed]
  17. Molybdenum cofactor deficiency presenting as neonatal hyperekplexia: a clinical, biochemical and genetic study. Macaya, A., Brunso, L., Fernández-Castillo, N., Arranz, J.A., Ginjaar, H.B., Cuenca-León, E., Corominas, R., Roig, M., Cormand, B. Neuropediatrics. (2005) [Pubmed]
  18. Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia. Rees, M.I., Harvey, K., Ward, H., White, J.H., Evans, L., Duguid, I.C., Hsu, C.C., Coleman, S.L., Miller, J., Baer, K., Waldvogel, H.J., Gibbon, F., Smart, T.G., Owen, M.J., Harvey, R.J., Snell, R.G. J. Biol. Chem. (2003) [Pubmed]
  19. Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB). Rees, M.I., Lewis, T.M., Kwok, J.B., Mortier, G.R., Govaert, P., Snell, R.G., Schofield, P.R., Owen, M.J. Hum. Mol. Genet. (2002) [Pubmed]
  20. Relaxation of glycine receptor and onconeural gene transcription control in NRSF deficient small cell lung cancer cell lines. Neumann, S.B., Seitz, R., Gorzella, A., Heister, A., Doeberitz, M.K., Becker, C.M. Brain Res. Mol. Brain Res. (2004) [Pubmed]
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