Erythrokeratoderma Variabilis Caused by p.Gly45Glu in Connexin 31: Importance of the First Extracellular Loop Glycine Residue for Gap Junction Function

Takeichi, Takuya; Sugiura, Kazumitsu; Hsu, Chao‐Kai; Nomura, Toshifumi; Takama, Hiroyuki; Simpson, Michael A.; Shimizu, Hiroshi; McGrath, John A.; Akiyama, Masashi

doi:10.2340/00015555-2307

Cited by 7 publications

(4 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This patient had no symptoms of hearing loss probably because this mutation in E2 domain is recessive. By systematically searching the PubMed, Embase and Web of Science, we summarized all the GJB3 mutations reported leading to EKV and phenotypes in each case ( Table 1 ) and autosomal dominant GJB3 mutation related to NSHL ( Figure 4 ; Richard et al, 1998 ; Xia et al, 1998 ; Wilgoss et al, 1999 ; Lopez-Bigas et al, 2000 ; Richard et al, 2000 ; Gottfried et al, 2002 ; Alexandrino et al, 2004 ; Terrinoni et al, 2004 ; Common et al, 2005 ; Feldmeyer et al, 2005 ; Morley et al, 2005 ; Yang et al, 2007 ; Renner et al, 2008 ; Li et al, 2010 ; Fuchs-Telem et al, 2011 ; Glatz et al, 2011 ; Scott and Kelsell, 2011 ; Wang et al, 2011 ; Liu et al, 2012 ; Torres et al, 2012 ; Wang et al, 2012 ; Ikeya et al, 2013 ; Oh et al, 2013 ; Otaguchi et al, 2014 ; Beck et al, 2015 ; Sugiura et al, 2015 ; Takeichi et al, 2016 ; Deng et al, 2018; Imura et al, 2020 ). In this case, the substitution of R98H lying in the border of M2 and CL, which are important in voltage and pH gating ( Richard et al, 2000 ), is the first mutation found involving both EKV and NSHL.…”

Section: Discussion and Literature Reviewmentioning

confidence: 98%

A Connexin Gene (GJB3) Mutation in a Chinese Family With Erythrokeratodermia Variabilis, Ichthyosis and Nonsyndromic Hearing Loss: Case Report and Mutations Update

Gao

Zhang

et al. 2022

Front. Genet.

View full text Add to dashboard Cite

Background: Gap junctions formed by connexins are channels on cytoplasm functioning in ion recycling and homeostasis. Some members of connexin family including connexin 31 are significant components in human skin and cochlea. In clinic, mutations of connexin 31 have been revealed as the cause of a rare hereditary skin disease called erythrokeratodermia variabilis (EKV) and non-syndromic hearing loss (NSHL).Objective: To determine the underlying genetic cause of EKV, ichthyosis and NSHL in three members of a Chinese pedigree and skin histologic characteristics of the EKV patient.Methods: By performing whole exome sequencing (WES), Sanger sequencing and skin biopsy, we demonstrate a Chinese pedigree carrying a mutation of GJB3 with three patients separately diagnosed with EKV, ichthyosis and NSHL.Results: The proband, a 6-year-old Chinese girl, presented with demarcated annular red-brown plaques and hyperkeratotic scaly patches on her trunk and limbs. Her mother has ichthyosis with hyperkeratosis and geographic tongue while her younger brother had NSHL since birth. Mutation analysis revealed all of them carried a heterozygous missense mutation c.293G>A of GJB3. Skin biopsy showed many grain cells with dyskeratosis in the granular layer. Acanthosis, papillomatosis, and a mild superficial perivascular lymphocytic infiltrate were observed.Conclusion: A mutation of GJB3 associated with EKV, ichthyosis and NSHL is reported in this case. The daughter with EKV and the son with NSHL in this Chinese family inherited the mutation from their mother with ichthyosis. The variation of clinical features may involve with genetic, epigenetic and environmental factors.

show abstract

Section: Discussion and Literature Reviewmentioning

confidence: 98%

A Connexin Gene (GJB3) Mutation in a Chinese Family With Erythrokeratodermia Variabilis, Ichthyosis and Nonsyndromic Hearing Loss: Case Report and Mutations Update

Gao

Zhang

et al. 2022

Front. Genet.

View full text Add to dashboard Cite

show abstract

“…Previously, we suggested that the chemical modifications of Cx46 extracellular Cys induce changes in this segment (between amino acids 47 and 61), which could be responsible for the closing of Cx46 hemichannels [ 41 ]. Moreover, mutations in this particular segment (also called the parahelix), especially in Gly45 in Cx31, are associated with Erythrokeratoderma variabilis [ 46 ] and in Cx26 is associated with keratitis–ichthyosis–deafness syndrome [ 47 ]. Similarly, mutations in Gly46 in Cx50 have been associated with cataract development [ 48 ], and mutations in positions 45 and 47 of Cx46 also have been associated with cataract formation [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

KI04 an Aminoglycosides-Derived Molecule Acts as an Inhibitor of Human Connexin46 Hemichannels Expressed in HeLa Cells

et al. 2023

View full text Add to dashboard Cite

Background: Connexins (Cxs) are proteins that help cells to communicate with the extracellular media and with the cytoplasm of neighboring cells. Despite their importance in several human physiological and pathological conditions, their pharmacology is very poor. In the last decade, some molecules derived from aminoglycosides have been developed as inhibitors of Cxs hemichannels. However, these studies have been performed in E. coli, which is a very simple model. Therefore, our main goal is to test whether these molecules have similar effects in mammalian cells. Methods: We transfected HeLa cells with the human Cx46tGFP and characterized the effect of a kanamycin-derived molecule (KI04) on Cx46 hemichannel activity by time-lapse recordings, changes in phosphorylation by Western blot, localization by epifluorescence, and possible binding sites by molecular dynamics (MD). Results: We observed that kanamycin and KI04 were the most potent inhibitors of Cx46 hemichannels among several aminoglycosides, presenting an IC50 close to 10 μM. The inhibitory effect was not associated with changes in Cx46 electrophoretic mobility or its intracellular localization. Interestingly, 5 mM DTT did not reverse KI04 inhibition, but the KI04 effect completely disappeared after washing out KI04 from the recording media. MD analysis revealed two putative binding sites of KI04 in the Cx46 hemichannel. Results: These results demonstrate that KI04 could be used as a Cx46 inhibitor and could help to develop future selective Cx46 inhibitors.

show abstract

“…Several studies indicate that ER stress is involved in this process . We describe how a rare EKV‐associated Cx31 mutant (G45E) causes necrotic cell death through a unique effect on the ER and entrapment of Cx43. We suggest that this may be a novel connexin‐mediated human disease mechanism.…”

Section: Introductionmentioning

confidence: 97%

“…The importance of connexins in the skin is illustrated by various disorders caused by mutations in different beta‐Cx subtypes . Erythrokeratodermia variabilis et progressiva (EKV‐P) (Mendes da Costa, EKV‐P, MIM #133200) is caused by heterozygous mutations in either Cx31 or Cx30.3, for example . The clinical appearance of EKV‐P ranges from temporary, fast‐moving erythemas to permanent red‐brown hyperkeratosis (Table ).…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Erythrokeratoderma Variabilis Caused by p.Gly45Glu in Connexin 31: Importance of the First Extracellular Loop Glycine Residue for Gap Junction Function

Cited by 7 publications

References 14 publications

A Connexin Gene (GJB3) Mutation in a Chinese Family With Erythrokeratodermia Variabilis, Ichthyosis and Nonsyndromic Hearing Loss: Case Report and Mutations Update

A Connexin Gene (GJB3) Mutation in a Chinese Family With Erythrokeratodermia Variabilis, Ichthyosis and Nonsyndromic Hearing Loss: Case Report and Mutations Update

KI04 an Aminoglycosides-Derived Molecule Acts as an Inhibitor of Human Connexin46 Hemichannels Expressed in HeLa Cells

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

Contact Info

Product

Resources

About