Connexin mutations in Brazilian patients with skin disorders with or without hearing loss

Abstract

The connexins are a family of proteins whose major function is as part of the gap junctions of cell-to-cell channels. They are expressed in several tissues including brain, skin, and cochlea. Mutations in connexin genes play a major role in non-syndromic sensorineural deafness, but have been also described in individuals with variable dermatological features. In recent years, many genes responsible for hereditary skin diseases have been discovered. These genes may encode different proteins that participate in the terminal differentiation of the epidermis. Therefore alteration or absence of these proteins causes a keratinization disorder. It has been demonstrated that distinct germline mutations within six connexin (Cx) genes GJB2 (Cx26), GJB6 (Cx30), GJB3 (Cx31), GJA1 (Cx43), GJB4 (Cx30.3), and GJB5 (Cx31.1), may cause sensorineural hearing loss and various skin disease phenotypes. The crucial functional importance of each of these connexins in the mentioned ectodermic tissues is reflected by the finding that genetic defects in their genes produce a wide spectrum of genetic disorders comprising sensorineural hearing loss, disorders of cornification of the skin, hair, and nails, and keratitis. Here, we report on different mutations in the connexin genes in individuals with or without hearing loss and different skin disorders illustrating the clinical and genetic heterogeneity of the condition.

In Search of Genetic Markers for Nonsyndromic Deafness in Africa: A Study in Cameroonians and Black South Africans with the GJB6 and GJA1 Candidate Genes

“…However, c.758C > T is a known change that is not considered to be pathogenic. It has been reported before in both cases and controls in various studies on GJA1 (Alexandrino et al, 2009;Paznekas et al, 2009;Kooshavar et al, 2012;Van Norstrand et al, 2012), but has been suggested to modify disease severity in certain cases (Cella et al, 2006).…”

Syndromic and non‐syndromic disease‐linked Cx43 mutations

“…In another case, the E42K mutation in Cx43 was found to be associated with sudden infant death syndrome which is thought to be linked to cardiac arrhythmias [69]. Finally, in a few very rare cases, reports have shown that GJA1 mutations can be associated with hearing loss and skin disorders with little or no evidence of ODDD [70–72].…”

Expression of connexins and the effect of retinoic acid in oral keratinocytes

“…The epidermis is primarily composed of keratinocytes, which temporally and spatially express as many as 10 different connexins, depending on their degree of differentiation (2,6). In addition, the importance of gap junctions in epidermal differentiation is supported by the discovery that mutations in gap junction proteins are the underlying cause of several inherited skin diseases (2,11). In rat epidermis, Cx26, Cx31, Cx31.1, Cx37, and Cx43 were demonstrated by immunofluorescence and Northern blot analysis (8), and Cx26, Cx30, Cx30.3, Cx31, Cx31.1, Cx32, Cx37, Cx40, Cx43, and Cx45 mRNAs have been detected in human epidermis (10), although Cx32 expression was low.…”

“…With SuperScript reverse transcriptase (GIBCO-BRL, NY, USA), complementary DNA was synthesized from 1 µg of total RNA in the presence of oligo (dT) [8][9][10][11][12] hexamer (Amersham Pharmacia Biotech, Buckinghamshire, UK) in a reaction volume of 20 µl at 37°C for 60 min. One microliter of cDNA solution was amplified with Ex Taq polymerase (Takara, Tokyo, Japan) in a volume of 12.5 µl, using each set of 20-µM primers.…”

“…In human epidermis, connexin genes encode different proteins that participate in terminal differentiation (2). In recent years, a number of connexin genes have been implicated in hereditary skin diseases (2,11). Cx26 and Cx43 were identified in the oral mucosal epithelium (7,(12)(13)(14); other subtypes of connexin have not yet been examined.…”