GJA1 gene

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Variants (also called mutations) in the GJA1 gene can cause the autosomal recessive form of craniometaphyseal dysplasia. This condition is characterized by a thickening of the bones in the skull (cranium) and a widening of a region at the end of the long bones known as the metaphysis. People who have the autosomal recessive form of craniometaphyseal dysplasia have a variant in both copies of the GJA1 gene. The most common variant changes a single protein building block (amino acid) in the connexin 43 protein: the amino acid arginine is replaced with the amino acid glutamine at position 239 (written as Arg239Gln or R239Q). It is unclear exactly how this variant in the GJA1 gene leads to the bone abnormalities that are seen in people with the autosomal recessive form of craniometaphyseal dysplasia.

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Variants in the GJA1 gene have been found to cause erythrokeratodermia variabilis et progressiva (EKVP) type 3, or EKVP3. EKVP3 is a skin disorder that is characterized by areas of abnormally thickened skin (hyperkeratosis), areas of skin that are darker than the surrounding skin (hyperpigmentation), and temporarily reddened patches of skin. Some affected individuals also develop palmoplantar keratoderma, which causes the skin on the palms of the hands and the soles of the feet to become thick, scaly, and calloused.

The variants that cause EKVP3 lead to the production of an abnormal version of the connexin 43 protein that is unable to reach the cell surface where it is needed. It is unclear how a shortage of connexin 43 at the cell surface affects the structure of gap junctions or how these changes result in the skin abnormalities seen in people with EKVP3. 

Many different variants in the GJA1 gene have been found to cause oculodentodigital dysplasia, a condition that is characterized by abnormalities of the eyes (oculo-), teeth (dento-), and fingers (digital). Many of these variants cause one amino acid to be substituted for another in connexin 43, which leads to the production of proteins that do not function properly. Some of these proteins disrupt the proper formation of the gap junction channels, while others alter the function of these channels. As a result, communication between cells is impaired. This lack of communication between cells early in development likely causes the eye, tooth, and finger abnormalities seen in people with oculodentodigital dysplasia.

Variants in the GJA1 gene can cause isolated syndactyly type III, which is characterized by the fusion of the ring and pinky fingers (the fourth and fifth fingers) and sometimes the shortening of the pinky finger. In most cases, the fourth and fifth fingers are connected by skin and soft tissue, but occasionally the bones of the fingers are fused together. Syndactyly type III is a feature of oculodentodigital dysplasia; however, some people have syndactyly type III without other features of oculodentodigital dysplasia (isolated syndactyly type III). It is unclear why some people with GJA1 gene variants develop only the finger abnormalities and others have the additional developmental abnormalities that are seen in people with oculodentodigital dysplasia.

A variant in one copy of the GJA1 gene has been found to cause palmoplantar keratoderma and congenital alopecia 1, a condition that is characterized by skin problems, an absence of hair from birth (congenital alopecia), and nail abnormalities. The variant identified in people with this disorder leads to the production of an altered connexin 43 protein. The channels that are made with the altered protein open more easily than normal, allowing more molecules to pass through them. Researchers suggest that abnormal signaling in the cells that form the skin, hair, and nails causes the features that are seen in people with palmoplantar keratoderma and congenital alopecia 1.