GJA1 Gene

GJA1 gene (GJA is the acronym for Gap Junction Protein Aalpha1 ) is a protein-coding gene located on chromosome 6q22.31. The GJA1 gene encodes connexin-43 (Cx43), one of the most abundant connexin proteins. Cxs are a family of transmembrane proteins with molecular masses ranging from 26 to 60 kD; Cx43 has a molecular mass of 43 kD. Connexin 43 is the major gap junction protein in the heart. Cardiac muscle cells are thought to be electrically coupled via gap junctions and to play a critical role in synchronous contraction of the heart and in embryonic development. A related intronless pseudogene is located on chromosome 5.

Diseases associated with GJA1 include:

• Erythrokeratodermia figurata variabilis et progressiva (AD) OMIM: 617525.
• Palmoplantar keratoderm congenital alopecia syndrome (AD) OMIM: 104100
• Atrioventricular septal defect 3 (AD) OMIM:600309
• Craniometaphyseal dysplasia, autosomal recessive (AR) OMIM:218400
• Hypoplastic left heart syndrome 1 (AR) OMIM: 241550
• Oculodentodigital dysplasia (AD) OMIM: 164200
• Oculodentodigital dysplasia, autosomal recessive (AR) OMIM: 257850
• Syndactyly, type III (AD) OMIM: 186100

Connexins, also called gap junction proteins, are phylogenetically very old integral membrane proteins and function, among other things, as structural proteins in the hexamer structures of gap junctions.

Connexins (Cxs) are a family of membrane-spanning proteins found in vertebrates and named for their molecular weight. They are involved in tissue homeostasis and act at multiple levels of communication.

Gap junctions are dodecameral channels that connect the cytoplasm of adjacent cells. They are formed by the docking of two hexameric hemichannels, one from each cell membrane. Gap junctions allow intercellular communication and enable cells to have synchronized responses to various intercellular signals. This is accomplished by regulating the influx or efflux of small molecules (< 1000 Da) as well as ions between the cytoplasms of adjacent cells.

In the skin, gap junctions are involved in the coordination of growth and differentiation of keratinocytes, among other things (see cell contacts below).

To date, more than 30 different connexins have been described in vertebrates. The most important connexins in human skin are connexin 43 (Cx43) and connexin 26 (Cx26). Cardiac Cxs are responsible for regular cardiac function, and among them, Cx26 and Cx43 are widely distributed throughout the heart.

1. Beyer EC et al. (2018) Gap junction gene and protein families: connexins, innexins and pannexins. Biochim. Biophys Acta Biomembr 1860: 5-8.
2. Boengler K et al (2017) Connexin 43 and mitochondria in cardiovascular health and disease. Adv Exp Med Biol 982: 227-246.
3. Boyden LM et al.(2015) Dominant de novo mutations in GJA1 cause erythrokeratodermia variabilis et progressiva, without features of oculodentodigital dysplasia. J Invest Derm 135: 1540-1547.
4. Cocozzelli AG et al (2019) Connexin 43 Mutations Lead to Increased Hemichannel Functionality in Skin Disease. Int J Mol Sci 20:6186
5. Xu J et al (2013) The role of connexins in ear and skin physiology - Functional insights from disease-associated mutation. Biomembranes 1828:167-178