The G60S Connexin43 Mutant Regulates Hair Growth and Hair Fiber Morphology in a Mouse Model of Human Oculodentodigital Dysplasia

Abstract

Patients expressing mutations in the gene encoding the gap junction protein Cx43 suffer from a disease called oculodentodigital dysplasia (ODDD). Patients with ODDD are often reported to develop hair that is dry, dull, sparse, and slow growing. To evaluate the linkage between Cx43 and hair growth, structure, and follicle density we employed a mouse model of ODDD that harbors a Cx43 G60S point mutant. Regionally sparse and overall dull hair were observed in mutant mice compared with their wild-type (WT) littermates. However, histological analysis of overall hair follicle density in mutant and WT mice did not reveal any significant differences. After epilation, mutant mouse hair grew back slower, and hair growth was asynchronous. In addition, ultrastructural scanning electron microscopic imaging of hair fibers taken from mutant mice and two patients harboring the G143S mutation revealed severe cuticle weathering. Nodule formation was also observed in the proximal region of hair fibers taken from mutant mice. These results suggest that the G60S mutant mouse model mimics the hair phenotype found in at least some ODDD patients and suggests an important role for Cx43 in hair regeneration, growth, and cuticle formation.

Syndromic and non‐syndromic disease‐linked Cx43 mutations

“…The G21R, G138R and the frame‐shift mutants are excellent examples of this class of mutants [89,92,99,102]. This situation has been shown to also occur in genetically‐modified mice that are heterozygous for the G60S mutant and mimic clinical features of ODDD [82,97,103,104].…”

“…Together with genetically matched littermate controls, Cx43 G60S mice have proven to be extremely valuable in providing insights into organ development and function, tissue differentiation, sub‐clinical disease, wound healing and several other pathophysiologies [82,93–95,103,104,114–120]. To that end, there has been numerous papers published using this novel mouse model of ODDD highlighting the versatility and importance of mouse models of human disease [82,93–95,103,104,114–120]. In many studies, cells were removed from vital organs and cultured to allow for cell and molecular assessment of GJIC and the potential dominant and/or transdominant effect the G60S mutant exhibited on co‐expressed wild‐type and other connexin family members.…”

Autosomal recessiveGJA1(Cx43) gene mutations cause oculodentodigital dysplasia by distinct mechanisms

“…Originally, ODDD was thought to be exclusively a disease linked to autosomal dominant mutations which would allow for the possibility that the allele harboring the wild-type gene could suffice to provide sufficient Cx43-based GJIC and allow patients to maintain essential organ function as seems to be the case in the heart where Cx43 is abundant (Gros and Jongsma, 1996). Many of these autosomal dominant mutants have been categorized by us and others as loss-of-function mutants, gain-of-hemichannel function mutants or dominant-negative mutants on co-expressed wild-type Cx43 (Churko et al, 2011a;Churko et al, 2012;Churko et al, 2010;Churko et al, 2011b;Dobrowolski et al, 2009;Dobrowolski et al, 2008;Dobrowolski et al, 2007;Flenniken et al, 2005;Gong et al, 2007;Gong et al, 2006;Lai et al, 2006;Langlois et al, 2007;Lorentz et al, 2012;Manias et al, 2008;McLachlan et al, 2005;McLachlan et al, 2008;Musa et al, 2009;Shao et al, 2012;Shibayama et al, 2005;Stewart et al, 2013;Toth et al, 2010). However, our understanding of the characteristics of Cx43 mutants became more complicated when two autosomal recessive mutations were identified that encoded a severely truncated Cx43 (R33X) (Richardson et al, 2006) and an arginine to a histidine (R76H) substitution within the domain predicted to be at the extreme region of the 1st extracellular loop (Pizzuti et al, 2004).…”

Connexin hemichannels influence genetically determined inflammatory and hyperproliferative skin diseases

“…For these mutations, inhibitor strategies may hold therapeutic value in addition to serving as research tools to pin down errors in channel gating and permselectivity (Figure 1). This concept is underscored by the topical accessibility of epidermal connexins and the fact that mouse models of Vohwinkel syndrome [28], EKV [29], ODDD [30], HED [31], and KID syndrome [32,33] already exist.…”