Connexin mutations in skin disease and hearing loss.
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ABSTRACT:
SUBMITTER: Kelsell DP
PROVIDER: S-EPMC1274469 | biostudies-literature | 2001 Mar
REPOSITORIES: biostudies-literature
Publications
Connexin mutations in skin disease and hearing loss.
Kelsell D P DP Di W L WL Houseman M J MJ
American journal of human genetics 20010125 3
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Project description:Gap junctional channels are specialized components of the cellular membrane that allow the intercellular passage of small metabolites, ions, and second messengers to maintain homeostasis. They are comprised of members of the connexin gene family that encode a wide array of proteins that are expressed in nearly every tissue type. Cx43 is perceived to be the most broadly expressed connexin in humans, with several genetic skin diseases being linked to Cx43 mutations specifically. These mutations, in large, produce a gain of functional hemichannels that contribute to the phenotypes of Erythrokeratoderma Variabilis et Progressiva (EKVP), Palmoplantar Keratodemra Congenital Alopecia-1 (PPKCA1), and others that produce large conductance and increased permselectivity in otherwise quiescent structures. Gaining functional hemichannels can have adverse effects in the skin, inducing apoptosis via Ca2+ overload or increased ATP permeability. Here, we review the link between Cx43 and skin disease. We aim to provide insight into the mechanisms regulating the normal and pathophysiological gating of these essential proteins, as well as address current therapeutic strategies. We also demonstrate that transient transfection of neuro-2a (N2a) cells with mutant Cx43 cDNA resulted in increased hemichannel activity compared to wild-type Cx43 and untransfected cells, which is consistent with other studies in the current literature.
| S-EPMC6940829 | biostudies-literature
Project description:The GJB2 gene is located on chromosome 13q12 and it encodes the connexin 26, a transmembrane protein involved in cell-cell attachment of almost all tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss. Moreover, it has been demonstrated that connexins are involved in regulation of growth and differentiation of epidermis and, in fact, GJB2 mutations have also been identified in syndromic disorders with hearing loss associated with various skin disease phenotypes. GJB2 mutations associated with skin disease are, in general, transmitted with a dominant inheritance pattern. Nonsyndromic deafness is caused prevalently by a loss-of-function, while literature evidences suggest for syndromic deafness a mechanism based on gain-of-function. The spectrum of skin manifestations associated with some mutations seems to have a very high phenotypic variability. Why some mutations can lead to widely varying cutaneous manifestations is poorly understood and in particular, the reason why the skin disease-deafness phenotypes differ from each other thus remains unclear. This review provides an overview of recent findings concerning pathogenesis of syndromic deafness imputable to GJB2 mutations with an emphasis on relevant clinical genotype-phenotype correlations. After describing connexin 26 fundamental characteristics, the most relevant and recent information about its known mutations involved in the syndromic forms causing hearing loss and skin problems are summarized. The possible effects of the mutations on channel expression and function are discussed.
| S-EPMC3219843 | biostudies-literature
Project description:Mutations in the connexin 26 (Cx26) gene (GJB2) are associated with the type of autosomal recessive nonsyndromic neurosensory deafness known as "DFNB1." Studies indicate that DFNB1 (13q11-12) causes 20% of all childhood deafness and may have a carrier rate as high as 2. 8%. This study describes the analysis of 58 multiplex families each having at least two affected children diagnosed with autosomal recessive nonsyndromic deafness. Twenty of the 58 families were observed to have mutations in both alleles of Cx26. Thirty-three of 116 chromosomes contained a 30delG allele, for a frequency of .284. This mutation was observed in 2 of 192 control chromosomes, for an estimated gene frequency of .01+/-.007. The homozygous frequency of the 30delG allele is then estimated at .0001, or 1/10,000. Given that the frequency of all childhood hearing impairment is 1/1,000 and that half of that is genetic, the specific mutation 30delG is responsible for 10% of all childhood hearing loss and for 20% of all childhood hereditary hearing loss. Six novel mutations were also observed in the affected population. The deletions detected cause frameshifts that would severely disrupt the protein structure. Three novel missense mutations, Val84Met, Val95Met, and Ser113Pro, were observed. The missense mutation 101T-->C has been reported to be a dominant allele of DFNA3, a dominant nonsyndromic hearing loss. Data further supporting the finding that this mutation does not cause dominant hearing loss are presented. This allele was found in a recessive family segregating independently from the hearing-loss phenotype and in 3 of 192 control chromosomes. These results indicate that 101T-->C is not sufficient to cause hearing loss.
| S-EPMC1377046 | biostudies-other
Project description:IntroductionSeveral studies have associated congenital sensorineural hearing loss in children with prolongation of the cardiac parameter QTc. The cause of this association is unknown. At the same time, mutations in GJB2, which encodes connexin 26, are the most common cause of congenital hearing impairment.ObjectiveTo compare electrocardiographic parameters (PR interval, QRS complex, and QTc interval) in patients with hearing loss who were tested for mutations in GJB2 and GJB6 to investigate whether these mutations affect electrical activity of the heart.Methods346 patients (176 males, 170 females) with sensorineural hearing loss of 30dB HL or more, aged 21.8±19.9 years (including 147 children <14 years), underwent both genetic study for GJB2 and GJB6 mutations and electrocardiography.ResultsMutations in GJB2, including homozygotes and heterozygotes, were found in 112 (32%) patients. There were no significant differences in ECG parameters between groups of patients with and without mutations in GJB2. No differences were observed either in men (mean PR with mutation: 155±16.6 vs. 153.6±30.1 without; QRS: 99.9±9.9 vs. 101.1±15.4; QTc: 414.9±29.9 vs. 412.4±25.7) or women (mean PR with: 148.7±21 vs. 143.8±22.8 without; QRS: 94.8±7.6 vs. 92.9±9.6; QTc: 416.8±20.6 vs. 424.9±22.8). In similar fashion, we did we find any significant differences between groups of children with and without GJB2 mutations (mean PR with: 126.3±19.6 vs. 127±19.7 without; QRS: 80.7±9.5 vs. 79.4±11.6; QTc: 419.7±23.5 vs. 419.8±24.8).ConclusionNo association was found between the presence of GJB2 mutations encoding connexin 26 in patients with hearing loss and their ECG parameters (PR, QRS, QTc).
| S-EPMC9442716 | biostudies-literature
Project description:ObjectivesTo document the audiologic phenotype of children with biallelic GJB2 (connexin 26) mutations, and to correlate it with the genotype.DesignProspective, observational study.SettingTertiary care children's hospital.PatientsInfants and children with sensorineural hearing loss (SNHL).InterventionSequencing of the GJB2 (connexin 26) gene.Main outcome measuresDegree and progression of SNHL.ResultsFrom December 1, 1998, through November 30, 2006, 126 children with biallelic GJB2 mutations were identified. Of the 30 different mutations identified, 13 (43%) were truncating and 17 (57%) were nontruncating; 62 patients had 2 truncating, 30 had 1 truncating and 1 nontruncating, and 17 had 2 nontruncating mutations. Eighty-four patients (67%) initially had measurable hearing in the mild to severe range in at least 1 of 4 frequencies (500, 1000, 2000, or 4000 Hz). Of these 84 patients with residual hearing, 47 (56%) had some degree of progressive hearing loss. Patients with 2 truncating mutations had significantly worse hearing compared with all other groups. Patients who had 1 or 2 copies of either an M34T or a V37I allele had the mildest hearing loss.ConclusionsHearing loss owing to GJB2 mutations ranges from mild to profound and is usually congenital. More than 50% of patients will experience some hearing loss progression, generally gradually but occasionally precipitously. Hearing loss severity may be influenced by genetic factors, such as the degree of preserved protein function in nontruncating mutations, whereas hearing loss progression may be dependent on factors other than the connexin 26 protein. Genetic counseling for patients with GJB2 mutations should include the variable audiologic phenotype and the possibility of progression.
| S-EPMC4528189 | biostudies-literature
Project description:Hearing impairment is the most common sensory disorder worldwide. In a recent study, the authors have shown that a heterozygous missense mutation, p.R184Q, in the connexin 26 (Cx26) is causally related to hearing loss. However, the functional change in the Cx26R184Q mutant remains unknown. This study compared the intracellular distribution and assembly of mutant Cx26R184Q with that of the wild-type (WT) Cx26 and Cx30WT in tet-on HeLa cells and the effect that the mutant protein had on those cells. Fluorescent localization assay of WT Cx26 showed the typical punctuate pattern of gap junction channel between neighboring expression cells. Conversely, the p.R184Q missense mutation resulted in accumulation of the Cx26 mutant protein in the Golgi apparatus rather than in the cytoplasmic membrane. Cx26R184Q coexpressed with either Cx26WT or Cx30WT showed perinuclear localization by bidirectional tet-on expression system, suggesting the impairment of the ability of both WT proteins to intracellular trafficking and targeting to the plasma membrane. Therefore, we proposed that Cx26R184Q has a dominant-negative effect on the function of WT Cx26 and Cx30.
| S-EPMC2987407 | biostudies-literature
Project description:Pathogenic mutations in the Gjb2 and Gjb6 genes, encoding connexin 26 (Cx26) and connexin 30 (Cx30), respectively, have been linked to the most frequent monogenic hearing impairment, nonsyndromic hearing loss, and deafness DFNB1. It is known that Cx26 plays an important role in auditory development, while the role of Cx30 in hearing remains controversial. Previous studies found that partial deletion of Cx26 can accelerate age-related hearing loss (ARHL), a multifactorial complex disorder, with both environmental and genetic factors contributing to the etiology of the disease. Here, we investigated the role of Cx30 in cochlear-aging processes using a transgenic mouse model with total deletion of Cx30 (Cx30 ΔΔ mice), in which Cx30 was removed without perturbing the surrounding sequences. We show that these mice are affected by exacerbated ARHL, with increased morphological cochlear damage, oxidative stress, inflammation, and vascular dysfunctions. Overall, our data demonstrate that Cx30 deletion can be considered a genetic risk factor for ARHL, making cochlear structures more susceptible to aging processes.
| S-EPMC9395607 | biostudies-literature
Project description:Although numerous causative genes for hereditary hearing loss have been identified, there are no fundamental treatments for this condition. Herein, we describe a novel potential treatment for genetic hearing loss. Because mutations or deletions in the connexin (Cx) genes are common causes of profound congenital hearing loss in both humans and mice, we investigated whether gene supplementation therapy using the wild-type Cx gene could cure hearing loss. We first generated inner ear-specific connexin 30 (Cx30)-deficient mice via the transuterine transfer of Cx30-targeted short hairpin RNA (shRNA-Cx30) into otocysts. The inner ear-specific Cx30-deficient mice mimicked homozygous Cx30-deficient mice both histologically and physiologically. Subsequently, we cotransfected the shRNA-Cx30 and the wild-type Cx30 gene. The cotransfected mice exhibited Cx30 expression in the cochleae and displayed normal auditory functions. Next, we performed the transuterine transfer of the wild-type Cx30 gene into the otocysts of homozygous Cx30-deficient mice, thereby rescuing the lack of Cx30 expression in the cochleae and restoring auditory functioning. These results demonstrate that supplementation therapy with wild-type genes can restore postnatal auditory functioning. Moreover, this is the first report to show that Cx-related genetic hearing loss is treatable by in vivo gene therapy.
| S-EPMC3677317 | biostudies-literature
Project description:Nonsyndromic hearing loss (NSHL) is of great clinical importance, and mutations in the GJB2 gene and the encoded human CONNEXIN 26 (CX26) protein play important roles in the genetic pathogenesis. The CX26 p.R184Q mutation was shown to be a dominant-negative effect in our previous study. Previously, we also demonstrated that zebrafish Cx30.3 is orthologous to human CX26. In the present study, we established transgenic zebrafish models with mutated Cx30.3 specifically expressed in the supporting cells of zebrafish inner ears driven by the agr2 promoter, to demonstrate and understand the mechanism by which the human CX26 R.184 mutation causes NSHL. Our results indicated that significant structural changes in the inner ears of transgenic lines with mutations were measured and compared to wild-type zebrafish. Simultaneously, significant alterations of transgenic lines with mutations in swimming behavior were analyzed with the zebrafish behavioral assay. This is the first study to investigate the functional results of the CX26 p.R184Q mutation with in vivo disease models. Our work supports and confirms the pathogenic role of the CX26 p.R184Q mutation in NSHL, with a hypothesized mechanism of altered interaction among amino acids in the connexins.
| S-EPMC7290585 | biostudies-literature
Project description:BackgroundHearing loss is the most common sensory disorder worldwide, affecting about 1 out of every 1000 newborns. The disease has major genetic components, and can be inherited as a single gene disorder either in autosomal dominant or recessive fashions. Due to the high rate of consanguineous unions, Iran has one of the highest prevalence of autosomal recessive nonsyndromic deafness (ARNSD) in the world.MethodsWe carried out a genetic screening of ten Iranian kindreds with more than one offspring affected by ARNSD caused by consanguineous unions. Sanger sequencing and whole exome sequencing together with in silico 3D structure modeling and protein stability prediction were used to identify the underlying disease causing genes.ConclusionWe identified the causes of deafness in all 10 kindred. In six kindreds homozygous mutations were identified in GJB2 gene by Sanger sequencing. By using whole exome sequencing (WES), a homozygous missense mutation was identified in ESRRB gene as the first ever reported disease gene in Iran. Also two novel homozygous frameshift and missense mutations were identified in MYO15A gene and one previously reported mutation in TMC1 gene in three independent kindred. Our study shows the efficacy of WES for unraveling new pathogenic mutations in ARNSD patients and expands the spectrum of genes contributing to ARNSD in the Iranian population. The findings of our study can facilitate future genetic screening of patients with ARNSD , early screening and optimal design of novel therapeutics.
| S-EPMC7987747 | biostudies-literature