GLRA1

The GLRA1 gene provides instructions for making one part, the alpha (α)1 subunit, of the glycine receptor protein. The glycine receptor is most abundant in 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 amino acid glycine. This molecule 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 cell. This influx of chloride ions reduces the cell's ability to transmit signals to other cells. Because they stop (inhibit) signaling, glycine receptors are known as inhibitory receptors.

hereditary hyperekplexia - caused by mutations in the GLRA1 gene

At least 29 mutations in the GLRA1 gene have been found to cause hereditary hyperekplexia. Most of these 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 prevents the receptor from opening. Other mutations prevent the receptor from reaching the cell membrane. When the glycine receptor is nonfunctional or missing, chloride ions cannot enter the cell, and cell signaling is increased. This overactive cell signaling in the spinal cord and brainstem is thought to cause the abnormal muscle movements, exaggerated startle reaction, and other symptoms of hereditary hyperekplexia.