From Hyperactive Connexin26 Hemichannels to Impairments in Epidermal Calcium Gradient and Permeability Barrier in the Keratitis-Ichthyosis-Deafness Syndrome

García, Isaac E.; Bosen, Felicitas; Mujica, Paula; Pupo, Amaury; Flores‐Muñoz, Carolina; Jara, Oscar; González, Carlos; Willecke, Klaus; Martı́nez, Agustı́n D.

doi:10.1016/j.jid.2015.11.017

Cited by 45 publications

(56 citation statements)

References 104 publications

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“…To our knowledge, our report is the first to detail the impact of this mutation on cellular integrity and provides evidence that disease progression is associated with necrotic cell death. We also show that the mutation has a trans‐dominant effect on the trafficking of Cx43 which, together with recent data for Cx26, suggest altered interaction with Cx43 may be indicative of severe Cx‐related skin disorders. Although the EKV‐P phenotype associated with this mutation is similar to other EKV‐P mutations reported, it is clear that the underlying mechanism attributed to the mutation is different, suggesting variable mechanisms of triggering the disease state and warrants further investigation.…”

Section: Discussionsupporting

confidence: 80%

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A rare missense mutation in GJB3 (Cx31G45E) is associated with a unique cellular phenotype resulting in necrotic cell death

Easton

Albuloushi

Kamps

et al. 2018

Experimental Dermatology

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Erythrokeratodermia variabilis et progressiva (EKV-P) is caused by mutations in either the GJB3 (Cx31) or GJB4 genes (Cx30.3). We identified a rare GJB3 missense mutation, c.134G>A (p.G45E), in two unrelated patients and investigated its cellular characteristics. Expression of Cx31G45E-GFP caused previously undescribed changes within HeLa cells and HaCaT cells, a model human keratinocyte cell line. Cx31WT-GFP localised to the plasma membrane, but expression of Cx31G45E-GFP caused vacuolar expansion of the endoplasmic reticulum (ER), the mutant protein accumulated within the ER membrane and disassembly of the microtubular network occurred. No ER stress responses were evoked. Cx31WT-myc-myc-6xHis and Cx31G45E-GFP co-immunoprecipitated, indicative of heteromeric interaction, but co-expression with Cx31WT-mCherry, Cx26 or Cx30.3 did not mitigate the phenotype. Cx31 and Cx31G45E both co-immunoprecipitated with Cx43, indicating the ability to form heteromeric connexons. WT-Cx31 and Cx43 assembled into large gap junction plaques at points of cell-to-cell contact; Cx31G45E restricted the ability of Cx43 to reach the plasma membrane in both HaCaT cells and HeLa cells stably expressing Cx43 where the proteins strongly co-localised with the vacolourised ER. Cell viability assays identified an increase in cell death in cells expressing Cx31G45E-GFP, which FACS analysis determined was necrotic. Blocking connexin channel function with 18α-glycyrrhetinic acid did not completely rescue necrosis or prevent propidium iodide uptake, suggesting that expression of Cx31G45E-GFP damages the cellular membrane independent of its channel function. Our data suggest that entrapment of Cx43 and necrotic cell death in the epidermis could underlie the EKV skin phenotype.

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Section: Discussionsupporting

confidence: 80%

“…Other mutations in Cx26, primarily associated with the amino‐terminal domain and the first part of first extracellular loop, are linked with KID syndrome. Recent studies indicate that a variety of Cx26 mutations have trans‐dominant effects on other epidermal connexins, including Cx43, inducing altered heteromeric channel function …”

Section: Discussionmentioning

confidence: 99%

A rare missense mutation in GJB3 (Cx31G45E) is associated with a unique cellular phenotype resulting in necrotic cell death

Easton

Albuloushi

Kamps

et al. 2018

Experimental Dermatology

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“…Abnormal connection channels can influence the movement of potassium ions back into the endolymph, altering potassium concentration to the point of intoxication of the organ of Corti, ultimately resulting in sensorineural deafness (Lefebvre and Van De Water, 2000). To date, many studies have indicated that mutations in the gene GJB2 can interrupt the transmission of second messengers such as inositol trisphosphate and calcium ions between cells, and the former is known to play an important role in auditory physiology (Beltramello et al, 2005;García et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Effect of GJB2 235delC and 30-35delG genetic polymorphisms on risk of congenital deafness in a Chinese population

et al. 2017

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ABSTRACT. Congenital deafness is a serious and irreversible condition in humans. The GJB2 gene is implicated in the pathogenesis of autosomal recessive nonsyndromic hearing loss. Its 235delC and 30-35delG polymorphisms are reported to be associated with risk of hereditary deafness. However, the effect of the interaction between GJB2 235delC and 30-35delG and environmental factors on congenital deafness has not been described. Therefore, we performed a casecontrol study to investigate the influence of these polymorphisms on congenital deafness risk, and their interaction with maternal and other environmental factors in the development of this disease. Between March 2014 and May 2015, 118 patients with congenital deafness and 242 healthy controls were enrolled into our study. Compared with the GG genotype, the adjusted odds ratios (ORs) [and 95% confidence intervals (CIs)] for the 235delC GC and CC genotypes were 4.66 (1.77-13.07) and 8.28 (2.06-47.52), respectively. Individuals harboring the GC+CC genotypes were at a greatly increased risk of congenital deafness compared to those with the GG genotype (OR = 5.65, 95%CI = 2.54-13.18). However, no significant relationship was established between the 30-35delG variant and this disease. The 235delC polymorphism exhibited an interaction with use of aminoglycoside antibiotics during pregnancy in conferring susceptibility to congenital deafness (chi-square = 8.76, P = 0.003). In conclusion, our study suggests that the GJB2 235delC polymorphism, but not the 30-35delG variant, contributes to congenital deafness susceptibility in the Chinese population examined, and demonstrates an interaction with consumption of aminoglycoside antibiotics during pregnancy in exerting this effect.

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“…The gap junction beta 2 ( GJB2; NM_004004.5) gene of 2250 base pairs (bp) comprises two exons of which one exon, exon two, encodes the short 226 amino acid protein connexin (Cx) 26. To date, nine mutations (3) in Cx26 have been reported to cause KID syndrome in altogether approximately 100 cases (4). The dominant mutation GJB2 c.148G > A, p.Asp50Asn is the most common one (5–9).…”

Section: Introductionmentioning

confidence: 99%

“…1). The GJB2 gene is expressed in various tissues throughout the body but Cx26 has specifically been demonstrated to be co-expressed with other Cx proteins (Cx30, Cx31 and Cx43) in human epidermal keratinocytes and cochlea (4,12,13), i.e. tissues where the KID phenotype is expressed.…”

Section: Introductionmentioning

confidence: 99%

Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26

Gudmundsson

Wilbe

Ekvall

et al. 2017

Human Molecular Genetics

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Revertant mosaicism (RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c.148G > A, p.Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultra-deep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p.Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p.Asp50Asn mutation. To our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.

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From Hyperactive Connexin26 Hemichannels to Impairments in Epidermal Calcium Gradient and Permeability Barrier in the Keratitis-Ichthyosis-Deafness Syndrome

Cited by 45 publications

References 104 publications

A rare missense mutation in GJB3 (Cx31G45E) is associated with a unique cellular phenotype resulting in necrotic cell death

A rare missense mutation in GJB3 (Cx31G45E) is associated with a unique cellular phenotype resulting in necrotic cell death

Effect of GJB2 235delC and 30-35delG genetic polymorphisms on risk of congenital deafness in a Chinese population

Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26

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