GABRA1

The GABRA1 gene provides instructions for making one piece, the alpha-1 (α1) subunit, of the GABA_A receptor protein. GABA_A receptors are made up of different combinations of five protein subunits, each produced from a different gene. (Nineteen different genes provide instructions for GABA_A receptor subunits.) These subunits form a hole (pore) in the cell membrane through which negatively charged chlorine atoms (chloride ions) can flow.

A chemical that transmits signals in the brain (a neurotransmitter) called gamma-amino butyric acid (GABA) attaches to GABA_A receptors. Once GABA attaches, the pore formed by the subunits opens, and chloride ions flow across the cell membrane. After infancy, chloride ions flow into the cell through the open pore, which creates an environment in the cell that blocks (inhibits) signaling between neurons. The primary role of GABA in children and adults is to prevent the brain from being overloaded with too many signals. In contrast, in newborns and infants, chloride ions flow out of the cell when the pore is opened, creating an environment that allows signaling between neurons.

juvenile myoclonic epilepsy - caused by mutations in the GABRA1 gene

A mutation in the GABRA1 gene has been identified in at least one family with juvenile myoclonic epilepsy. This condition typically begins in childhood or adolescence and causes recurrent myoclonic seizures, which are characterized by rapid, uncontrolled muscle jerks. Affected individuals can also have other types of seizures called generalized tonic-clonic seizures (or grand mal seizures) and absence seizures. The mutation associated with this condition changes a single protein building block (amino acid) in the α1 subunit. The amino acid alanine at protein position 322 is replaced by the amino acid asparagine. This gene mutation is written as Ala322Asp or A322D.

This GABRA1 gene mutation leads to the formation of an abnormal α1 subunit that reduces GABA_A receptor function. GABA_A receptors containing the abnormal subunit are broken down before they reach the cell membrane. Studies show that the altered receptors can also interfere with normal receptors inside the cell, leading to the additional loss of normal receptors. Because of the reduction of GABA_A receptor function, signaling between neurons is not regulated, which can lead to overstimulation of neurons. Researchers believe that the overstimulation of certain neurons in the brain triggers the abnormal brain activity associated with seizures.