Defective Epidermal Barrier in Neonatal Mice Lacking the C-Terminal Region of Connexin43

Maass, Karen; Ghanem, Alexander; Kim, Jung-Sun; Saathoff, Manuela; Urschel, Stephanie; Kirfel, Gregor; Grümmer, Ruth; Kretz, Markus; Lewalter, Thorsten; Tiemann, Klaus; Winterhager, Elke; Herzog, Volker; Willecke, Klaus

doi:10.1091/mbc.e04-04-0324

Cited by 127 publications

(153 citation statements)

References 72 publications

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“…However, until 2005 no Cx43-ODDD linked mutations were reported in the GJA1 gene encoding the large 148 amino acid C-terminal tail of Cx43, which led to speculations that this domain was either resistance to mutation or mutants in this region were embryonic lethal. Mice lacking Cx43 or expressing a truncated version of Cx43 where the last 125 amino acids are lost, die within the first week after birth suggesting that dysregulation of Cx43 can lead to premature death at least in mouse models (23,38). In the present study, we characterize a newly reported frameshift mutation in the C terminus of FIGURE 5.…”

Section: Discussionmentioning

confidence: 75%

“…Given that the last native 123 amino acid residues are lost from this frameshift Cx43 mutant it is postulated that the reason for patients suffering from increased disease burden may be related to a critical role played by the Cx43 C terminus in the skin. In fact, mice expressing a Cx43 mutant where the last 125 amino acids of Cx43 are missing die within 1 week after birth because of the loss of skin barrier function (23).…”

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confidence: 99%

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Functional Characterization of aGJA1Frameshift Mutation Causing Oculodentodigital Dysplasia and Palmoplantar Keratoderma

Gong¹,

Shao²,

Lounsbury³

et al. 2006

J. Biol. Chem.

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A frameshift mutation generated from a dinucleotide deletion (780 -781del) in the GJA1 gene encoding Cx43 results in a frameshift yielding 46 aberrant amino acids after residue 259 and a shortened protein of 305 residues compared with the 382 in wild-type Cx43. This frameshift mutant (fs260) causes oculodentodigital dysplasia (ODDD) that includes the added condition of palmoplantar keratoderma. When expressed in a variety of cell lines, the fs260 mutant was typically localized to the endoplasmic reticulum and other intracellular compartments. The fs260 mutant, but not the G138R ODDD-linked Cx43 mutant or a Cx43 mutant truncated at residue 259 (T259), reduced the number of apparent gap junction plaques formed from endogenous Cx43 in normal rat kidney cells or keratinocytes. Interestingly, mutation of a putative FF endoplasmic reticulum retention motif encoded within the 46 aberrant amino acid domain failed to restore efficient assembly of the fs260 mutant into gap junctions. Dual whole cell patch-clamp recording revealed that fs260-expressing N2A cells exerted severely reduced electrical coupling in comparison to wild-type Cx43 or the T259 mutant, whereas single patch capacitance recordings showed that fs260 could also dominantly inhibit the function of wild-type Cx43. Co-expression studies further revealed that the dominant negative effect of fs260 on wild-type Cx43 was dose-dependent, and at a predicted 1:1 expression ratio the fs260 mutant reduced wild-type Cx43-mediated gap junctional conductance by over 60%. These results suggest that the 46 aberrant amino acid residues associated with the frameshift mutant are, at least in part, responsible for the manifestation of palmoplantar keratoderma symptoms.Gap junctions are unique intercellular channels that directly connect the cytoplasm of neighboring cells, which are formed by integral membrane proteins called connexins (Cxs) 2 (1). Each apposing cell contributes a hexameric arrangement of connexins, also known as a connexon, which dock to form a gap junction channel. A connexin polypeptide chain spans the plasma membrane four times, consisting of four transmembrane domains (M1 to M4), two extracellular loops (EL-1 and EL-2) and one intracellular loop (IL), with both the N and C termini (AT and CT, respectively) located in the cytoplasm (2-4) (Fig. 1). Whereas connexin transmembrane domains and extracellular loops are highly conserved, the intracellular loop and C terminus are known to be the most variable domains across different connexin family members, suggesting that these domains play important roles in the differential functions of connexins.Connexins exhibit complex tissue distribution patterns that are temporally and spatially regulated during development and differentiation. Among connexin family members (21 in human and 20 in mouse), the GJA1-encoded protein (Cx43) exhibits the most ubiquitous distribution, playing important roles in many tissue types and physiological processes (5). Cx43 channels can be regulated by a pH-sensitive "ball-and-chain" mec...

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Section: Discussionmentioning

confidence: 75%

mentioning

confidence: 99%

Functional Characterization of aGJA1Frameshift Mutation Causing Oculodentodigital Dysplasia and Palmoplantar Keratoderma

Gong¹,

Shao²,

Lounsbury³

et al. 2006

J. Biol. Chem.

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“…Thus, the comparison of the 2 tissue types presents a number of interesting candidates that either play a causative role in the barrier dysfunction or regulate the response to this state. We chose to focus our investigation on the gap junction protein Cx26 because of the potential biological significance of gap junctions in human disorders, wound healing, and development and its possible role in barrier acquisition (15,23,24,32).…”

Section: Resultsmentioning

confidence: 99%

Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response

Djalilian¹

2006

Journal of Clinical Investigation

111

107

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Inflammatory skin disorders result in significant epidermal changes, including keratinocyte hyperproliferation, incomplete differentiation, and impaired barrier. Here we test whether, conversely, an impaired epidermal barrier can promote an inflammatory response. Mice lacking the transcription factor Kruppel-like factor 4 (Klf4) have a severe defect in epidermal barrier acquisition. Transcription profiling of Klf4 -/-newborn skin revealed similar changes in gene expression to involved psoriatic plaques, including a significant upregulation of the gap junction protein connexin 26 (Cx26). Ectopic expression of Cx26 from the epidermis-specific involucrin (INV) promoter (INV-Cx26) demonstrated that downregulation of Cx26 is required for barrier acquisition during development. In juvenile and adult mice, persistent Cx26 expression kept wounded epidermis in a hyperproliferative state, blocked the transition to remodeling, and led to an infiltration of immune cells. Mechanistically, ectopic expression of Cx26 in keratinocytes resulted in increased ATP release, which delayed epidermal barrier recovery and promoted an inflammatory response in resident immune cells. These results provide a molecular link between barrier acquisition in utero and epidermal remodeling after wounding. More generally, these studies suggest that the most effective treatments for inflammatory skin disorders might concomitantly suppress the immune response and enhance epidermal differentiation to restore the barrier.

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“…Subsequent studies delineate the abnormal cardiac morphogenetic process and changes in blood pressure and heart rate [Guerrero et al, 1997;Ya et al, 1998;Liao et al, 2001]. Mice with a homozygous lack of the carboxyl-terminal portion of Cx43 (K258X) [Maass et al, 2004] die shortly after birth (o3% survival to adulthood) due to a defect of the epidermal barrier resulting from lack of terminal keratinocyte differentiation brought about by the prolonged half life of mutant Cx43 gap junction channels in the upper layers of the epidermis. Surviving females are infertile, having impaired antral stage formation in folliculogenesis, and corpora lutea formation occurs without ovulation.…”

Section: Introductionmentioning

confidence: 99%

GJA1mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype

et al. 2009

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The predominantly autosomal dominant disorder, oculodentodigital dysplasia (ODDD) has high penetrance with intra-and interfamilial phenotypic variability. Abnormalities observed in ODDD affect the eye, dentition, and digits of the hands and feet. Patients present with a characteristic facial appearance, narrow nose, and hypoplastic alae nasi. Neurological problems, including dysarthria, neurogenic bladder disturbances, spastic paraparesis, ataxia, anterior tibial muscle weakness, and seizures, are known to occur as well as conductive hearing loss, cardiac defects, and anomalies of the skin, hair, and nails. In 2003, our analysis of 17 ODDD families revealed that each had a different mutation within the human gap junction alpha 1 (GJA1) gene which encodes the protein connexin 43 (Cx43). Since then at least 17 publications have identified an additional 26 GJA1 mutations and in this study, we present 28 new cases with 18 novel GJA1 mutations. We include tables summarizing the 62 known GJA1 nucleotide changes leading to Cx43 protein alterations and the phenotypic information available on 177 affected individuals from 54 genotyped families. Mutations resulting in ODDD occur in each of the nine domains of the Cx43 protein, and we review our functional experiments and those in the literature, examining the effects of 13 different Cx43 mutations upon gap junction activity.

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Defective Epidermal Barrier in Neonatal Mice Lacking the C-Terminal Region of Connexin43

Cited by 127 publications

References 72 publications

Functional Characterization of aGJA1Frameshift Mutation Causing Oculodentodigital Dysplasia and Palmoplantar Keratoderma

Functional Characterization of aGJA1Frameshift Mutation Causing Oculodentodigital Dysplasia and Palmoplantar Keratoderma

Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response

GJA1mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype

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