Article

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

ABSTRACT

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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    • "In the first group, PPK with deafness[28], Vohwinkel syndrome (VS)[56], and Bart–Pumphrey syndrome (BP)[57]are thought to represent phenotypic subtypes within a spectrum , and the pathogenic mutations among the three diseases overlap and mainly affect the first extracellular loop (Fig. 2). Clinically , they are similar as well, with palmoplantar keratoderma and deafness, but without the widespread keratoderma seen in keratitis–ichthyosis–deafness syndrome or hystrix-like ichthyosis deafness syndrome[58]. PPK, VS and BP have a few distinguishing characteristics, which led to their different categorization, but it is unclear how important these characteristics are. Palmoplantar keratoderma develops in infancy in VS, in childhood in BP. "
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    ABSTRACT: Gap junctions and hemichannels comprised of connexins influence epidermal proliferation and differentiation. Significant advances in our understanding of the functional role of connexins in the skin have been made by studying the diseases caused by connexin mutations. Eleven clinically defined cutaneous disorders with an overlapping spectrum of phenotypes are caused by mutations in five different connexin genes, highlighting that disease presentation must be deciphered with an understanding of how connexin functions are affected. Increasing evidence suggests that the skin diseases produced by connexin mutations result from dominant gains of function. In palmoplantar keratoderma with deafness, the connexin 26 mutations transdominantly alter the function of wild-type connexin 43 and create leaky heteromeric hemichannels. In keratitis-ichthyosis-deafness syndrome, different connexin 26 mutations can either form dominant hemichannels with altered calcium regulation or increased calcium permeability, leading to clinical subtypes of this syndrome. It is only with detailed understanding of these subtle functional differences that we can hope to create successful pathophysiology driven therapies for the connexin skin disorders.
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    • "Mutations in this gene are the most common cause of hereditary nonsyndromic hearing impairment, causing up to 50% of autosomal recessive cases [1] [2] and up to 37% of unknown cause [3]. Also, although infrequently, mutations in this gene cause genetic syndromes that affect hearing and skin [4] [5]. "
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    ABSTRACT: The mutations in the GJB2 gene are the most common cause of nonsyndromic hearing impairment and they are associated with the population’s ethnic background. The p.Val27Ile is frequent in both Asia and America. In this retrospective study, we report the findings from the GJB2 screening and the audiological exams conducted on 125 Mexican mestizo patients with non-syndromic hearing impairment; they were treated at the Instituto Nacional de Rehabilitacion in Mexico City. The most frequent audiometric findings were bilateral, symmetrical, and profound hearing impairment. The allele frequencies in the GJB2 screening were p.Val27Ile 15%, other mutations 5%, and wild type 80%. We found no correlation between GJB2 genotype and auditory phenotype. The high allele frequency of p.Val27Ile was a very interesting finding. Our research suggests that p.Val27Ile arose in an ancient common ancestor who lived in Altai Republic and then the polymorphism was brought to America by its first inhabitants, the Amerindians. These results enhance our understanding of the peopling of the America, which remains unresolved.
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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.
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