Human diseases associated with connexin mutations

Abstract

Gap junctions and hemichannels comprised of connexins impact many cellular processes. Significant advances in our understanding of the functional role of these channels have been made by the identification of a host of genetic diseases caused by connexin mutations. Prominent features of connexin disorders are the inability of other connexins expressed in the same cell type to compensate for the mutated one, and the ability of connexin mutants to dominantly influence the activity of other wild-type connexins. Functional studies have begun to identify some of the underlying mechanisms whereby connexin channel mutation contributes to the disease state. Detailed mechanistic understanding of these functional differences will help to facilitate new pathophysiology driven therapies for the diverse array of connexin genetic disorders. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.

Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity

“…In all cases these results have been derived from visual inspection and using an inclusive criterion. Also, in Table 2 we associate our findings with the recently reported [11, 12] functional state of Cx26 hemichannels, gap-junctions and pathological phenotypes [64]. It is important to notice that due to the three-dimensional approach used here to identify the possible associations between reported mutations and calcium-biding sites from the MD simulations, some mutations are at a distant region of the sequence from that where we find calcium binding sites.…”

“…GLU120 and ASP159. Moreover, a number of calcium binding sites are one or two residues apart from a reported mutation site [11, 12, 15, 62–64]. While these observations are important, it is also relevant to take into account the three-dimensional nature of our problem.…”

“…Multiple pathologies and developmental disorders, such as hearing loss, skin diseases, peripheral and central neuropathic disorders, lens cataracts (Cx26, Cx30) and cardiac arrhythmias (Cx40), have been associated with different dysfunctions of hemichannels and GJCs [11–13]. Many of these pathologies are associated to specific genetic variants that change the Cx amino acid sequence [11, 12]. For example, two clinical phenotypes were associated to hearing loss due to Cx26 hemichannel malfunction [14] and a heterozygous missense mutation was identified in a family with dominant deaf-mutism and palmoplantar keratoderma [15].…”

Endoplasmic Reticulum Stress in Hearing Loss

“…The most well-known deafness condition associated with impaired ER stress is caused by mutations in genes encoding WFS1 and connexins [57][58][59]. Recently, it was shown that impaired ER stress is also involved in Usher (USH) syndrome [60,61].…”

“…In vertebrates, gap junction proteins known as connexins are encoded by nearly 20 genes [82]. Mutations in connexin genes have been shown to associate with various types of disease, including peripheral neuropathy, skin disease, cataracts, and hearing loss [59]. Mutations in GJB2, which encodes for connexin 26 (Cx26), contribute tõ 50% of autosomal recessive nonsyndromic hearing loss [83][84][85][86][87][88].…”