Connexin-26 mutations in deafness and skin disease

Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, New York 11794-8661, USA.
Expert Reviews in Molecular Medicine (Impact Factor: 5.15). 11/2009; 11:e35. DOI: 10.1017/S1462399409001276
Source: PubMed


Gap junctions allow the exchange of ions and small molecules between adjacent cells through intercellular channels formed by connexin proteins, which can also form functional hemichannels in nonjunctional membranes. Mutations in connexin genes cause a variety of human diseases. For example, mutations in GJB2, the gene encoding connexin-26 (Cx26), are not only a major cause of nonsyndromic deafness, but also cause syndromic deafness associated with skin disorders such as palmoplantar keratoderma, keratitis-ichthyosis deafness syndrome, Vohwinkel syndrome, hystrix-ichthyosis deafness syndrome and Bart-Pumphrey syndrome. The most common mutation in the Cx26 gene linked to nonsyndromic deafness is 35DeltaG, a frameshift mutation leading to an early stop codon. The large number of deaf individuals homozygous for 35DeltaG do not develop skin disease. Similarly, there is abundant experimental evidence to suggest that other Cx26 loss-of-function mutations cause deafness, but not skin disease. By contrast, Cx26 mutations that cause both skin diseases and deafness are all single amino acid changes. Since nonsyndromic deafness is predominantly a loss-of-function disorder, it follows that the syndromic mutants must show an alteration, or gain, of function to cause skin disease. Here, we summarise the functional consequences and clinical phenotypes resulting from Cx26 mutations that cause deafness and skin disease.

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    • "For functioning mutants of hCx26 and other connexins that cause human pathology, the resulting channels generally have altered gating of hemichannels and GJCs and/or evidence of altered molecular permeability (Lee and White, 2009; Martinez et al., 2009). Dysfunction of the signaling communication mediated by connexin channels can also become evident only in the context of other nongenetic pathological conditions, such as ischemia, trauma/inflammation, and neuropathic pain, in which unbalanced or altered connexin expression or function potentiates tissue dysfunction and damage (De Maio et al., 2002; Contreras et al., 2004; Bennett et al., 2012; Chen et al., 2012). "
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    ABSTRACT: Connexin channels mediate electrical coupling, intercellular molecular signaling, and extracellular release of signaling molecules. Connexin proteins assemble intracellularly as hexamers to form plasma membrane hemichannels. The docking of two hemichannels in apposed cells forms a gap junction channel that allows direct electrical and selective cytoplasmic communication between adjacent cells. Hemichannels and junctional channels are gated by voltage, but extracellular Ca (2+) also gates unpaired plasma membrane hemichannels. Unlike other ion channels, connexin channels do not contain discrete voltage- or Ca (2+)-sensing modules linked to a separate pore-forming module. All studies to date indicate that voltage and Ca (2+) sensing are predominantly mediated by motifs that lie within or are exposed to the pore lumen. The sensors appear to be integral components of the gates, imposing an obligatory structural linkage between sensing and gating not commonly present in other ion channels, in which the sensors are semi-independent domains distinct from the pore. Because of this, the structural and electrostatic features that define connexin channel gating also define pore permeability properties, and vice versa; analysis/mutagenesis of gating and of permeability properties are linked. This offers unique challenges and opportunities for elucidating mechanisms of ligand and voltage-driven gating.
    Frontiers in Physiology 03/2014; 5:113. DOI:10.3389/fphys.2014.00113 · 3.53 Impact Factor
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    • "More recent work demonstrated connexin hemichannel functions under physiological conditions (Bruzzone et al., 2001; Anselmi et al., 2008; Garré et al., 2010) and evidence for channel independent function, e.g., in cell growth and death (Vinken et al., 2012) or migration (Kameritsch et al., 2012). Mutations in connexins were discovered in inherited human diseases like oculodentodigital dysplasia (ODDD, Cx43, GJA1; Huang et al., 2013), X-linked Charcot-Marie-Tooth disease (Cx32, GJB1; Scherer and Kleopa, 2012), Pelizaeus-Merzbacher-like disease or a milder spastic paraplegia (Cx47; Kleopa et al., 2010), Vohwinkel syndrome as well as Keratitis-Icthyosis-Deafness (KID) syndrome (Cx26, GJB2; Lee and White, 2009; Xu and Nicholson, 2013), Erythrokeratodermia variabilis (Cx31, GJB3; Cx30.3, GJB4), Clouston syndrome (Cx30, GJB6) or secondary lymphedema following breast cancer treatment (Cx47, GJC2; Finegold et al., 2012). Furthermore, transcriptional and post-transcriptional alterations and dysfunctional degradation by autophagy (Lichtenstein et al., 2011; Fong et al., 2012) may represent indirect mechanisms causing impaired GJC. "
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    ABSTRACT: Gap junction communication (GJC) mediated by connexins is critical for heart function. To gain insight into the causal relationship of molecular mechanisms of disease pathology, it is important to understand which mechanisms contribute to impairment of gap junctional communication. Here, we present an update on the known modulators of connexins, including various interaction partners, kinases, and signaling cascades. This gap junction network (GJN) can serve as a blueprint for data mining approaches exploring the growing number of publicly available data sets from experimental and clinical studies.
    Frontiers in Physiology 02/2014; 5:82. DOI:10.3389/fphys.2014.00082 · 3.53 Impact Factor
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    • "Cx26 is expressed in a number of tissues, and its mutations are frequently associated with deafness and skin diseases (Forge and Wright, 2002; Forge et al., 2003; Gerido and White, 2004; Zhao et al., 2006; Nickel and Forge, 2008; Lee and White, 2009; Liu et al., 2009). Here we will focus on the role of Cx26 in the inner ear. "
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    ABSTRACT: Gap-junction channels (GJCs) are aqueous channels that communicate adjacent cells. They are formed by head-to-head association of two hemichannels (HCs), one from each of the adjacent cells. Functional HCs are connexin hexamers composed of one or more connexin isoforms. Deafness is the most frequent sensineural disorder, and mutations of Cx26 are the most common cause of genetic deafness. Cx43 is the most ubiquitous connexin, expressed in many organs, tissues, and cell types, including heart, brain, and kidney. Alterations in its expression and function play important roles in the pathophysiology of very frequent medical problems such as those related to cardiac and brain ischemia. There is extensive information on the relationship between phosphorylation and Cx43 targeting, location, and function from experiments in cells and organs in normal and pathological conditions. However, the molecular mechanisms of Cx43 regulation by phosphorylation are hard to tackle in complex systems. Here, we present the use of purified HCs as a model for functional and structural studies. Cx26 and Cx43 are the only isoforms that have been purified, reconstituted, and subjected to functional and structural analysis. Purified Cx26 and Cx43 HCs have properties compatible with those demonstrated in cells, and present methodologies for the functional analysis of purified HCs reconstituted in liposomes. We show that phosphorylation of serine 368 by PKC produces a partial closure of the Cx43 HCs, changing solute selectivity. We also present evidence that the effect of phosphorylation is highly cooperative, requiring modification of several connexin subunits, and that phosphorylation of serine 368 elicits conformational changes in the purified HCs. The use of purified HCs is starting to provide critical data to understand the regulation of HCs at the molecular level.
    Frontiers in Physiology 02/2014; 5:71. DOI:10.3389/fphys.2014.00071 · 3.53 Impact Factor
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