The GFAP gene provides instructions for making GFAP protein, a member of the intermediate filament family that provides support and strength to cells. Several molecules of GFAP protein bind together to form the main intermediate filament found in specialized brain cells called astrocytes. Astrocytes are star-shaped cells that support the functions of nerve cells in the brain and spinal cord (central nervous system). If the central nervous system is injured through trauma or disease, astrocytes react by rapidly producing more GFAP.
Although its function is not fully understood, GFAP protein is probably involved in controlling the shape and movement of astrocytes. The protein probably also plays a significant role in the interactions of astrocytes with other cells, which are required for the formation and maintenance of the insulating layer (myelin) that covers nerve cells. Additionally, GFAP protein may assist in maintaining the protective barrier that allows only certain substances to pass between blood vessels and the brain (blood-brain barrier).
Of the 3 subtypes of Alexander disease (infantile, juvenile, and adult), all three have been proven to be caused by mutations in GFAP. More than 20 GFAP mutations that cause Alexander disease have been identified. These mutations change a single amino acid (the building material of proteins) in the GFAP protein. The most frequent changes affect arginine at position 79 or 239 in the protein's chain of amino acids. In these positions, arginine is often replaced by cysteine or histidine. The change of a single amino acid can alter properties of the GFAP protein, such as how it interacts with other proteins. The altered GFAP protein may block the normal assembly of intermediate filaments and other proteins that contribute to the structure of astrocytes.
However, it remains unclear how mutations in the GFAP gene lead to Alexander disease. Blocked assembly of intermediate filaments and other structural proteins may lead to protein deposits inside the cell. The deposited proteins, called Rosenthal fibers, may then interfere with normal astrocyte functions such as astrocyte interactions with other specialized cells in the brain. The disrupted interactions probably result in the inability to maintain or form myelin and to maintain the blood-brain barrier.
The gene for GFAP is on chromosome 17 in band 17q21.