A novel mutation in the connexin 26 gene (<i>GJB2</i>) in a child with clinical and histological features of keratitis–ichthyosis–deafness (KID) syndrome

Koppelhus, Uffe; Tranebjærg, Lisbeth; Esberg, Gitte; Ramsing, Mette; Lodahl, Marianne; Rendtorff, Nanna Dahl; Olesen, Hanne Vebert; Sommerlund, Mette

doi:10.1111/j.1365-2230.2010.03936.x

Cited by 35 publications

(39 citation statements)

References 24 publications

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“…KID patients have recurrent cutaneous infections that lead to lethal septicemia in severe cases where individuals carry the Cx26-G45E or Cx26-A88V mutations (15,18,20,38). Some cases of KID syndrome also show additional features comprising the follicular occlusion triad (dissecting folliculitis, hidradenitis suppurativa, and cystic acne) or display an increased incidence of squamous cell carcinoma (26,31,44).…”

Section: Discussionmentioning

confidence: 95%

“…Cx26-A88V has been described in two pediatric patients with the lethal form of KID syndrome. These children had congenital deafness, alopecia, severe hyperkeratosis, and recurrent skin infections that eventually lead to septicemia and death in early childhood (15,20). Using two different electrophysiological assays, we show that both Cx26-D50A and Cx26-A88V form active hemichannels that significantly increase membrane current flow compared with wild-type Cx26.…”

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confidence: 93%

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The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity

Mhaske

Levit

et al. 2013

American Journal of Physiology-Cell Physiology

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Mutations in the human gene encoding connexin 26 (Cx26 or GJB2) cause either nonsyndromic deafness or syndromic deafness associated with skin diseases. That distinct clinical disorders can be caused by different mutations within the same gene suggests that different channel activities influence the ear and skin. Here we use three different expression systems to examine the functional characteristics of two Cx26 mutations causing either mild (Cx26-D50A) or lethal (Cx26-A88V) keratitis-ichthyosis-deafness (KID) syndrome. In either cRNA-injected Xenopus oocytes, transfected HeLa cells, or transfected primary human keratinocytes, we show that both Cx26-D50A and Cx26-A88V form active hemichannels that significantly increase membrane current flow compared with wild-type Cx26. This increased membrane current accelerated cell death in low extracellular calcium solutions and was not due to increased mutant protein expression. Elevated mutant hemichannel currents could be blocked by increased extracellular calcium concentration. These results show that these two mutations exhibit a shared gain of functional activity and support the hypothesis that increased hemichannel activity is a common feature of human Cx26 mutations responsible for KID syndrome.

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 93%

The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity

Mhaske

Levit

et al. 2013

American Journal of Physiology-Cell Physiology

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“…For example, mutations in Cx26 and Cx30 result in Keratitis-ichthyosis-deafness, a disease that is characterized by progressive corneal opacification, either mild generalized hyperkeratosis or discrete erythematous plaques, and neurosensory deafness. 8 Mutations in Cx32 cause X-linked Charcot-Marie-Tooth disease, which is characterized as motor and sensory neuropathy. 9 Multiple lines of evidence suggest that connexins could be targeted pharmacologically for treating many diseases.…”

Section: Introductionmentioning

confidence: 99%

A High-Throughput Assay for Connexin 43 (Cx43,GJA1) Gap Junctions Using Codon-Optimized Aequorin

Haq

Grose²,

Ward³

et al. 2013

ASSAY and Drug Development Technologies

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Gap junctions (GJs) are intercellular channels which are composed of the connexin family of proteins that allow electrical and chemical communications and synchronization in tissue ensembles. Evidence suggests that pharmaceutical modulators of these channels may have therapeutic potential or carry undesired liability. In this report, we exogenously expressed human connexin 43 (Cx43, GJA1) and demonstrated functionality in a 96-well flow cytometry assay detecting intercellular transfer of the calcein dye. We have designed a 384-well high-throughput method for detecting the transfer of calcium between HeLa cells expressing Cx43. In this assay, donor cells coexpress Cx43 and the α1A adrenergic Gα-coupled receptor, while recipient cells coexpress Cx43 and the cytoplasmic version of the calcium-sensitive luminescent protein aequorin enhanced by codon optimization (cytoAeq). The two cell populations were mixed, dispensed to 384-well plates, and incubated for 3 h to allow the formation of GJs. Activation of α1A by epinephrine in donor cells led to dose-dependent calcium increases in recipient cells, which were detected by measuring the intensity of aequorin luminescence. The response was dependent on the expression of Cx43 and inhibited by the GJ blocker 18α-glycyrrhetinic acid, suggesting Cx43 GJ-mediated activity. In a parallel experiment with capsaicin and the TrpV1 ion channel in place of phenylephrine and α1A, a similar magnitude of difference in the maximal calcium response was detected in both donor and recipient cells, suggesting that calcium is likely the permeant ion through the GJ. This assay may pave the way for high-throughput screening of GJ modulators for drug discovery.

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“…One of the most severe forms arises from the A88V mutation which leads to the hyper-proliferation of the skin, defects in the retina and deafness associated with this disease [28]. This form is so severe it results in sepsis and death during infancy [28,29]. Individuals with this mutation have also been shown to experience loss of respiratory drive consistent with a defect in their CO 2 chemosensitivity.…”

Section: Connexin 26: Carbamates For Conformational Changementioning

confidence: 97%

“…In the skin, Keratitis-ichthyosis-deafness (KID) syndrome is linked to several point mutations in Cx26 [27]. One of the most severe forms arises from the A88V mutation which leads to the hyper-proliferation of the skin, defects in the retina and deafness associated with this disease [28]. This form is so severe it results in sepsis and death during infancy [28,29].…”

Section: Connexin 26: Carbamates For Conformational Changementioning

confidence: 98%

CO2 carbamylation of proteins as a mechanism in physiology

Meigh

2015

Biochemical Society Transactions

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Carbamate bonds occur following the nucleophilic attack of CO2 on to an amine. In proteins, this can occur at lysine side chains or at the N-terminus. For CO2 binding to occur an amine must be present in the NH2 form and consequently carbamates represent a site-specific post-translational modification, occurring only in environments of reduced hydration. Due to the specific nature of these interactions, coupled with the inability of these bonds to survive protein preparation methods, carbamate reactions appear rare. However, more biologically important examples continue to emerge that use carbamates as key parts of their mechanisms. In this review, we discuss specific examples of carbamate bond formation and their biological consequences with an aim to highlight this important, and often forgotten, biochemical group.

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A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis–ichthyosis–deafness (KID) syndrome

Abstract: This study has identified a new heterozygous de novo mutation in the Cx26 gene (c.263C>T; p.Ala88Val) leading to KID syndrome.

Cited by 35 publications

References 24 publications

The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity

The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity

A High-Throughput Assay for Connexin 43 (Cx43,GJA1) Gap Junctions Using Codon-Optimized Aequorin

CO2 carbamylation of proteins as a mechanism in physiology

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