GJB2

The GJB2 gene provides instructions for making a protein called gap junction beta 2, more commonly known as connexin 26. Connexin 26 is a member of the connexin protein family. Connexin proteins form channels called gap junctions that permit the transport of nutrients, charged atoms (ions), and signaling molecules between neighboring cells. The size of the gap junction and the types of particles that move through it are determined by the particular connexin proteins that make up the channel. Gap junctions made with connexin 26 transport potassium ions and certain small molecules.

Connexin 26 is found in cells throughout the body, particularly in the inner ear and the skin. Because of its presence in the inner ear, especially the snail-shaped structure called the cochlea, researchers are interested in this protein's role in hearing. Hearing requires the conversion of sound waves to electrical nerve impulses. This conversion involves many processes, including maintaining the proper level of potassium ions in the inner ear. Some studies indicate that channels made with connexin 26 help to maintain the correct level of potassium ions. Other research suggests that connexin 26 is required for the maturation of certain cells in the cochlea. The GJB2 gene also plays a role in the growth and maturation of the outermost layer of skin (the epidermis).

nonsyndromic deafness - caused by mutations in the GJB2 gene

Researchers have identified more than 90 GJB2 mutations that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB1. DFNB1 deafness is inherited in an autosomal recessive manner, which means that two copies of the GJB2 gene in each cell are altered. GJB2 mutations probably alter gap junctions, which may disturb the level of potassium ions in the inner ear. Levels of potassium ions that are too high may affect the function and survival of cells that are needed for hearing.

Some mutations delete or insert DNA building blocks (base pairs) within or near the GJB2 gene. The most common mutation, particularly in the Caucasian (white) population, deletes one base pair between positions 30 and 35 in the GJB2 gene (written as 35delG or 30delG). In Asian populations, a frequently reported mutation deletes a base pair at position 235 (235delC). Among people with an eastern European (Ashkenazi) Jewish ancestry, a base-pair deletion at position 167 (167delT) is a common mutation. These deletions lead to an abnormally small protein that cannot form functional gap junctions.

Other GJB2 mutations replace one of the protein building blocks (amino acids) used to make connexin 26 with an incorrect amino acid. These mutations lead to an unstable or misshapen protein that cannot form gap junctions, or an altered protein that forms dysfunctional gap junctions.

Researchers have also identified several GJB2 mutations that cause a form of nonsyndromic deafness called DFNA3, which is inherited in an autosomal dominant manner. This type of inheritance means that one copy of the GJB2 gene in each cell is altered. These mutations replace one amino acid in connexin 26 with an incorrect amino acid. It remains unclear how these GJB2 mutations lead to DFNA3 hearing loss. The altered connexin 26 protein probably inhibits the assembly of gap junctions or their normal function, which could disrupt the conversion of sound waves to nerve impulses.

other disorders - caused by mutations in the GJB2 gene

GJB2 mutations have also been identified in people with certain skin abnormalities. These mutations replace one of the protein building blocks (amino acids) used to make connexin 26 with an incorrect amino acid. The altered connexin 26 protein probably disrupts the assembly of gap junctions. This disruption could affect skin growth and also impair hearing by disturbing the conversion of sound waves to nerve impulses.

Two GJB2 mutations have been reported in people with Vohwinkel syndrome, a condition characterized by hearing loss and thickened skin, particularly on the knuckles. One mutation replaces the amino acid aspartic acid with the amino acid histidine at protein position 66 (written as Asp66His or D66H). The other mutation replaces the amino acid glycine with the amino acid valine at protein position 130 (Gly130Val or G130V).

Researchers have also reported GJB2 mutations in individuals with palmoplantar keratoderma with deafness, a condition in which the skin on the palms and soles is unusually thick. These mutations include replacing glycine with the amino acid alanine at position 59 (Gly59Ala or G59A) and replacing the amino acid arginine with the amino acid glutamine at position 75 (Arg75Gln or R75Q).

Bart-Pumphrey syndrome is another skin condition caused by GJB2 mutations. This condition is characterized by a white discoloration of the nails (leukonychia), thickened skin on the palms and soles, small lumps on the knuckles (knuckle pads), and hearing loss. The GJB2 mutations replace glycine with the amino acid serine at protein position 59 (Gly59Ser or G59S) or replace the amino acid asparagine with the amino acid lysine at protein position 54 (Asn54Lys or N54K).

Several GJB2 mutations that cause keratitis-ichthyosis-deafness (KID) syndrome have been identified. This syndrome is characterized by fishlike scaling of the skin, inflammation of the front surface of the eye (cornea), and deafness. These mutations also involve changing one of the amino acids in connexin 26.