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: 5.91). 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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    ABSTRACT: Connexins (Cxs) form a family of transmembrane proteins comprising 21 members in humans. Cxs differ in their expression patterns, biophysical properties and ability to combine into homomeric or heteromeric gap junction channels between neighboring cells. The permeation of ions and small metabolites through gap junction channels or hemichannels confers a crucial role to these proteins in intercellular communication and in maintaining tissue homeostasis. Among others, Cx37, Cx40, Cx43, Cx45 and Cx47 are found in heart, blood- and lymphatic vessels. Mutations or polymorphisms in the genes coding for these Cxs have not only been implicated in cardiovascular pathologies but also in a variety of other disorders. While mutations in Cx43 are mostly linked to oculodentodigital dysplasia, Cx47 mutations are associated with Pelizaeus-Merzbacher-like disease and lymphedema. Cx40 mutations are principally linked to atrial fibrillation. Mutations in Cx37 have not yet been described, but polymorphisms in the Cx37 gene have been implicated in the development of arterial disease. This review addresses current knowledge on gene mutations in cardiovascular Cxs systematically and links them to alterations in channel properties and disease.This article is protected by copyright. All rights reserved
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    ABSTRACT: Die Kombination von sensorineuraler Schwerhörigkeit und Keratosen an Händen und Füßen ist selten. Wir berichten im Folgenden über ein im Neugeborenen-Hörscreening aufgefallenes Kind, welches Keratosen an Händen und Füßen aufwies. Familienanamnestisch fiel beim Vater dieselbe Symptomkonstellation auf. Sie ist typisch für das Keratoma hereditarium mutilans, einer autosomal-dominant vererbten Erkrankung mit Mutation des Gens GJB2, welches für das Protein Connexin 26 kodiert und in unserem Fall höchstwahrscheinlich als Spontanmutation im Genom des Vaters an die Tochter vererbt wurde.
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