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Normal Function
The GLRA1 gene provides instructions for making one part, the alpha (α)1 subunit, of the glycine receptor protein. The glycine receptor is embedded in the membrane of nerve cells (neurons) in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). The glycine receptor is made up of five subunits: two α1 subunits and three beta (β) subunits. The β subunit is produced from a different gene.
Receptor proteins have specific sites into which certain other molecules, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function. The ligand for the glycine receptor is the protein building block (amino acid) glycine. This molecule also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the nervous system.
When glycine attaches (binds) to the glycine receptor, the receptor opens to allow negatively charged chlorine atoms (chloride ions) to enter the neuron. This influx of chloride ions reduces the neurons's ability to transmit signals to other neurons. Because they stop (inhibit) signaling, glycine receptors are known as inhibitory receptors.
Health Conditions Related to Genetic Changes
Hereditary hyperekplexia
More than 60 mutations in the GLRA1 gene have been found to cause hereditary hyperekplexia. This condition is most often seen in infants who experience increased muscle tone (hypertonia) and an exaggerated startle reaction to unexpected stimuli, especially loud noises. The startle reaction can trigger a brief period of rigidity and immobility, and in some cases, infants stop breathing. Most GLRA1 gene mutations change single amino acids in the α1 subunit of the glycine receptor protein. The most common mutation replaces the amino acid arginine with the amino acid leucine at protein position 271 (written as Arg271Leu or R271L).
GLRA1 gene mutations that cause hereditary hyperekplexia impair the ability of the glycine receptor protein to respond to the ligand glycine. Some GLRA1 gene mutations alter the structure of the glycine receptor, which can prevent the receptor from opening or cause it to open without the presence of glycine. Other mutations prevent the receptor from reaching the cell membrane. When the glycine receptor is dysfunctional or missing, chloride ions enter the cell when they are not needed or cannot enter the cell at all. The resulting increase in cell signaling in the spinal cord and brainstem likely causes the abnormal muscle movements, exaggerated startle reaction, and other signs and symptoms of hereditary hyperekplexia.
More About This Health ConditionOther Names for This Gene
- GLRA1_HUMAN
- glycine receptor, alpha 1
- glycine receptor, alpha 1 isoform 1 precursor
- glycine receptor, alpha 1 isoform 2 precursor
- STHE
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Balint B, Thomas R. Hereditary Hyperekplexia Overview. 2007 Jul 31 [updated 2019 Dec 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK1260/ Citation on PubMed
- Bode A, Wood SE, Mullins JGL, Keramidas A, Cushion TD, Thomas RH, Pickrell WO, Drew CJG, Masri A, Jones EA, Vassallo G, Born AP, Alehan F, Aharoni S, Bannasch G, Bartsch M, Kara B, Krause A, Karam EG, Matta S, Jain V, Mandel H, Freilinger M, Graham GE, Hobson E, Chatfield S, Vincent-Delorme C, Rahme JE, Afawi Z, Berkovic SF, Howell OW, Vanbellinghen JF, Rees MI, Chung SK, Lynch JW. New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms. J Biol Chem. 2013 Nov 22;288(47):33745-33759. doi: 10.1074/jbc.M113.509240. Epub 2013 Oct 9. Citation on PubMed or Free article on PubMed Central
- Harvey RJ, Topf M, Harvey K, Rees MI. The genetics of hyperekplexia: more than startle! Trends Genet. 2008 Sep;24(9):439-47. doi: 10.1016/j.tig.2008.06.005. Epub 2008 Aug 15. Citation on PubMed
- Masri A, Chung SK, Rees MI. Hyperekplexia: Report on phenotype and genotype of 16 Jordanian patients. Brain Dev. 2017 Apr;39(4):306-311. doi: 10.1016/j.braindev.2016.10.010. Epub 2016 Nov 11. Citation on PubMed
- Villmann C, Oertel J, Melzer N, Becker CM. Recessive hyperekplexia mutations of the glycine receptor alpha1 subunit affect cell surface integration and stability. J Neurochem. 2009 Nov;111(3):837-47. doi: 10.1111/j.1471-4159.2009.06372.x. Epub 2009 Sep 1. Citation on PubMed
- Zhang Y, Bode A, Nguyen B, Keramidas A, Lynch JW. Investigating the Mechanism by Which Gain-of-function Mutations to the alpha1 Glycine Receptor Cause Hyperekplexia. J Biol Chem. 2016 Jul 15;291(29):15332-41. doi: 10.1074/jbc.M116.728592. Epub 2016 May 18. Citation on PubMed or Free article on PubMed Central
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