Mutations in cardiovascular connexin genes

Abstract

Connexins (Cxs) form a family of transmembrane proteins comprising 21 members in humans. Cxs differ in their expression patterns, biophysical properties and ability to combine into homomeric or heteromeric gap junction channels between neighbouring cells. The permeation of ions and small metabolites through gap junction channels or hemichannels confers a crucial role to these proteins in intercellular communication and in maintaining tissue homeostasis. Among others, Cx37, Cx40, Cx43, Cx45 and Cx47 are found in heart, blood and lymphatic vessels. Mutations or polymorphisms in the genes coding for these Cxs have not only been implicated in cardiovascular pathologies but also in a variety of other disorders. While mutations in Cx43 are mostly linked to oculodentodigital dysplasia, Cx47 mutations are associated with Pelizaeus-Merzbacher-like disease and lymphoedema. Cx40 mutations are principally linked to atrial fibrillation. Mutations in Cx37 have not yet been described, but polymorphisms in the Cx37 gene have been implicated in the development of arterial disease. This review addresses current knowledge on gene mutations in cardiovascular Cxs systematically and links them to alterations in channel properties and disease.

Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection

“…In the heart atrial fibrillation may result from mutations in Cx40 (Molica et al, 2014). Cxs also play prominent roles in acquired diseases.…”

Interaction Between ALK1 Signaling and Connexin40 in the Development of Arteriovenous Malformations

“…Gap junction proteins form channels between neighboring cells to allow direct intercellular exchanges of ions and small metabolites, which are needed to coordinate vasoconstriction and vasodilation along the vessels. 38,39 Genetic studies show that mice lacking Cx40 develop hypertension because of increased secretion of renin and reduced relaxation of peripheral vessels. 40 These defects have recently been shown to be at least partially dependent on endothelial Cx40 function indicating that Cx40 expression levels regulate blood pressure.…”

“…19 Genetic polymorphisms have been detected in both promoter regions of GJA5 and suspected to be associated with risk of cardiovascular diseases, including hypertension. 39 These polymorphisms have been shown to affect GJA5 promoter activity by reducing gene expression by approximately half with interassay variations ranging from 20% to 65% reduction. By comparing the expression levels of Cx40 in sections of human skin biopsies isolated from 5 healthy donors and 4 patients with HHT2, we have confirmed that important differences exist between individuals, and more importantly, we reveal that Cx40 protein levels are particularly low in the majority of a small selection of patients with HHT2 compared with the healthy donors supporting an association between ALK1 signaling and Cx40 expression.…”

Pannexin- and Connexin-Mediated Intercellular Communication in Platelet Function

“…Cxs are members of a family of proteins encoded by 20 to 21 different mammalian genes, which are expressed in a large variety of tissues [89,90]. Cx genes are classified according to sequence homology and are divided into five subfamilies [91]; cardiovascular Cxs belong mostly to the α subfamily ( GJA ).…”