Two de novo GJA1 mutation in two sporadic patients with erythrokeratodermia variabilis et progressiva

Li, Changxing; Liang, Jingyao; Chen, Pingjiao; Zeng, Kang; Xue, Rujun; Xiang, Tian; Liang, Li-Fang; Wang, Qi; Shi, Minglan; Zhang, Xibao

doi:10.1002/mgg3.670

Cited by 10 publications

(22 citation statements)

References 26 publications

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“…Investigations of the mechanism for EKVP involve Cx43-A44V and Cx43-E227D, which have been reported to result in hemichannel localization failure and subsequent Golgi accumulation [73]. Two new mutations have since been discovered and are attributable to EKVP as well, producing similar phenotypes in cases [74]. In PPKCA1, Cx43-G8V has been reported to increased hemichannel activity, resulting in increased basal levels of Ca 2+ and its permeability [75].…”

Section: Cx43 Hemichannelsmentioning

confidence: 99%

Connexin 43 Mutations Lead to Increased Hemichannel Functionality in Skin Disease

Cocozzelli

White

2019

IJMS

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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.

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Section: Cx43 Hemichannelsmentioning

confidence: 99%

Connexin 43 Mutations Lead to Increased Hemichannel Functionality in Skin Disease

Cocozzelli

White

2019

IJMS

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“…While these lesions are not life-threatening, they cause substantial morbidity due to pain and irritation. EKVP is genetically heterogenous with linkages to seven genes that include three connexin-encoding genes: GJB3 (Cx31) [ 9 , 10 , 11 , 12 , 13 ], GJB4 (Cx30.3) [ 4 , 14 , 15 , 16 ], and GJA1 (Cx43) [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, two novel de novo autosomal dominant missense variants in GJA1 (p.P283L and p.T290N) were identified in two unrelated Chinese patients with EKVP [ 18 ]. In both cases, these variants were not detected in unaffected family members and 100 unrelated controls, and no variants were identified in GJB3 or GJB4 [ 18 ], although other genes linked to EKVP were not investigated [ 26 , 27 , 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Interrogation of Carboxy-Terminus Localized GJA1 Variants Associated with Erythrokeratodermia Variabilis et Progressiva

Lucaciu

Shao

Figliuzzi

et al. 2022

IJMS

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Although inherited GJA1 (encoding Cx43) gene mutations most often lead to oculodentodigital dysplasia and related disorders, four variants have been linked to erythrokeratodermia variabilis et progressiva (EKVP), a skin disorder characterized by erythematous and hyperkeratotic lesions. While two autosomal-dominant EKVP-linked GJA1 mutations have been shown to lead to augmented hemichannels, the consequence(s) of keratinocytes harboring a de novo P283L variant alone or in combination with a de novo T290N variant remain unknown. Interestingly, these variants reside within or adjacent to a carboxy terminus polypeptide motif that has been shown to be important in regulating the internalization and degradation of Cx43. Cx43-rich rat epidermal keratinocytes (REKs) or Cx43-ablated REKs engineered to express fluorescent protein-tagged P283L and/or T290N variants formed prototypical gap junctions at cell–cell interfaces similar to wildtype Cx43. Dye coupling and dye uptake studies further revealed that each variant or a combination of both variants formed functional gap junction channels, with no evidence of augmented hemichannel function or induction of cell death. Tracking the fate of EKVP-associated variants in the presence of the protein secretion blocker brefeldin A, or an inhibitor of protein synthesis cycloheximide, revealed that P283L or the combination of P283L and T290N variants either significantly extended Cx43 residency on the cell surface of keratinocytes or delayed its degradation. However, caution is needed in concluding that this modest change in the Cx43 life cycle is sufficient to cause EKVP, or whether an additional underlying mechanism or another unidentified gene mutation is contributing to the pathogenesis found in patients. This question will be resolved if further patients are identified where whole exome sequencing reveals a Cx43 P283L variant alone or, in combination with a T290N variant, co-segregates with EKVP across several family generations.

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“…Some of these patients even have severely compromised Cx43 function as many Cx43 mutants are dominant to the functional status of co-expressed wild type Cx43 [ 47 , 48 ]. However, Cx43 pathologies can occasionally affect the skin as a set of patients have been identified that harbor GJA1 mutations and present with erythrokeratodermia variabilis et progressiva (EKVP) [ 49 , 50 , 51 ]. These patients suffer from transient erythematous patches and hyperkeratotic plaques [ 49 , 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, Cx43 pathologies can occasionally affect the skin as a set of patients have been identified that harbor GJA1 mutations and present with erythrokeratodermia variabilis et progressiva (EKVP) [ 49 , 50 , 51 ]. These patients suffer from transient erythematous patches and hyperkeratotic plaques [ 49 , 50 , 51 ]. Subsequent studies have assigned hyperactive Cx43 hemichannels as the potential cause of this skin pathology [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Cx31 and Cx43 in Differentiation-Competent Rodent Keratinocytes

Shao

White

et al. 2020

Biomolecules

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When considering connexin expression and regulation, the epidermis of the skin is one of the most complex tissues found in mammals even though it largely contains a single cell type, the keratinocyte. In the rodent epidermis, up to 9 connexin family members have been detected at the mRNA level. Many of these connexins are temporally and spatially regulated in coordination with keratinocyte progenitor cell differentiation and migration from the stratum basale to form the stratum spinosum and stratum granulosum layers before finally forming the stratum corneum. Cx43 is the principal connexin found in basal keratinocytes and to a lesser degree found in keratinocytes that have begun to differentiate where Cx26, Cx30 and Cx31 become prevalent. Here we show that the CRISPR-Cas9 ablation of Cx43 reduces overall gap junction coupling in monolayer cultures of rat epidermal keratinocytes (REKs) and dysregulates the differentiation of REKs when grown in organotypic cultures. Natively found in differentiated keratinocytes, Cx31 readily assembles into gap junctions when expressed in REKs where it can extensively co-assemble into the same gap junctions with co-expressed Cx30. Time-lapse imaging indicated that many Cx31 gap junctions are mobile within the plasma membrane undergoing both fusion and fission events. Finally, the persistence of pre-existing Cx31 gap junctions in the presence of the protein trafficking blocker, brefeldin A, is longer than that found for Cx43 gap junctions indicating that it has a distinctly different life expectancy in REKs. Collectively, this study highlights the importance of Cx43 in rodent keratinocyte differentiation and suggests that Cx31 acquires life-cycle properties that are distinct from Cx43.

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Two de novo GJA1 mutation in two sporadic patients with erythrokeratodermia variabilis et progressiva

Cited by 10 publications

References 26 publications

Connexin 43 Mutations Lead to Increased Hemichannel Functionality in Skin Disease

Connexin 43 Mutations Lead to Increased Hemichannel Functionality in Skin Disease

Interrogation of Carboxy-Terminus Localized GJA1 Variants Associated with Erythrokeratodermia Variabilis et Progressiva

Comparative Analysis of Cx31 and Cx43 in Differentiation-Competent Rodent Keratinocytes

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