Skin changes in oculo‐dento‐digital dysplasia are correlated with C‐terminal truncations of connexin 43

Vreeburg, Maaike; Zwart-Storm, Eugene A. de; Schouten, Meyke; Nellen, Ruud G. L.; Marcus-Soekarman, D.; Devies, M.; Geel, Michel van; Steensel, M.A.M. van

doi:10.1002/ajmg.a.31558

Cited by 56 publications

(41 citation statements)

References 7 publications

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“…Although ODDD patients are usually not affected with skin symptoms, the fs260 mutation has been reported to be associated with palmoplantar keratoderma (van Steensel et al, 2005). More recently, it has been shown that skin changes in ODDD are correlated with Cterminal truncations of Cx43 (Vreeburg et al, 2007). Together, these data suggest that the association of Cx43 with Cav-1 in keratinocytes might play a functional role during epidermal differentiation.…”

Section: Discussionmentioning

confidence: 95%

Caveolin-1 and -2 Interact with Connexin43 and Regulate Gap Junctional Intercellular Communication in Keratinocytes

Langlois

Cowan

Shao

et al. 2008

MBoC

113

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Connexin43 (Cx43) has been reported to interact with caveolin (Cav)-1, but the role of this association and whether other members of the caveolin family bind Cx43 had yet to be established. In this study, we show that Cx43 coimmunoprecipitates and colocalizes with Cav-1 and Cav-2 in rat epidermal keratinocytes. The colocalization of Cx43 with Cav-1 was confirmed in keratinocytes from human epidermis in vivo. Our mutation and Far Western analyses revealed that the C-terminal tail of Cx43 is required for its association with Cavs and that the Cx43/Cav-1 interaction is direct. Our results indicate that newly synthesized Cx43 interacts with Cavs in the Golgi apparatus and that the Cx43/Cavs complex also exists at the plasma membrane in lipid rafts. Using overexpression and small interfering RNA approaches, we demonstrated that caveolins regulate gap junctional intercellular communication (GJIC) and that the presence of Cx43 in lipid raft domains may contribute to the mechanism modulating GJIC. Our results suggest that the Cx43/Cavs association occurs during exocytic transport, and they clearly indicate that caveolin regulates GJIC. INTRODUCTIONGap junctions are specialized intercellular membrane channels that allow direct transfer of molecules of Ͻ1000 Dalton to selectively pass from one cell to another (Sohl and Willecke, 2004;Laird, 2005). Gap junctional intercellular communication (GJIC) plays a critical role in the coordination of development, tissue function, and cell homeostasis (Segretain and Falk, 2004;Wei et al., 2004). Gap junction channels are composed of two hemichannels, termed connexons, each provided by one of the two contacting cells and each connexon is composed of six transmembrane proteins, called connexins (Cxs) (Laird, 2006). The large gene family encoding Cx comprises 21 members in human (Sohl and Willecke, 2004;Wei et al., 2004). Cx43 is the most abundant gap junction protein in a wide spectrum of tissues, including the epidermis (Kretz et al., 2004;Laird, 2006). Cx43 is most likely assembled into connexons in the trans-Golgi network and then traffics along microtubules to the plasma membrane where they diffuse laterally and aggregate into gap junction plaques (Saez et al., 2003;Martin and Evans, 2004;Segretain and Falk, 2004;Laird, 2006;Lauf et al. 2002), although one report suggests that Cx43 containing vesicles may be directly targeted to adherens junctions adjacent to gap junctions (Shaw et al., 2007). The function of existing gap junction channels can be controlled by their opening and closing, whereas the regulation of their delivery, assembly, and removal constitutes additional mechanisms to control GJIC (Saez et al., 2003;Segretain and Falk, 2004;Laird, 2006). The extent of intercellular coupling is thus finely regulated by the control of connexin channels present at the plasma membrane, their functional state, and their permeability. All of these properties are determined by the constituent proteins of the connexon and their interaction with other protein partners and lipids (Cascio, ...

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Section: Discussionmentioning

confidence: 95%

Caveolin-1 and -2 Interact with Connexin43 and Regulate Gap Junctional Intercellular Communication in Keratinocytes

Langlois

Cowan

Shao

et al. 2008

MBoC

113

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“…1A) (16) with the resulting disease outcome being classified as ODDD highlighted by developmental defects in the craniofacial bones around the eyes and nose, loss of enamel resulting in early destruction of the teeth, and lack of soft tissue separation of two or three digits (14). In addition to these commonly found developmental disorders, patients often exhibit an assortment of conditions that range broadly from neurological to cardiac disorders (14,(21)(22)(23)(24). It is possible that epigenetic effects may also contribute to these disease states.…”

Section: Autosomal Dominant Mutationsmentioning

confidence: 99%

“…It is possible that epigenetic effects may also contribute to these disease states. Interestingly, in cases in which the patient harbors a frameshift mutation (fs230 (24) or fs260 (25)) resulting in a gross deletion of the C terminus of Cx43, these individuals have an increased disease load of palmoplantar keratodermas or palmar hyperkeratosis not unlike what is found in some patients harboring dominant GJB2 mutations. The fact that one point mutation in Cx43 (L11P) (26) has been associated with hyperkeratosis suggests that the added disease load in the skin is not restricted solely to the events linked to the C terminus of the molecule.…”

Section: Autosomal Dominant Mutationsmentioning

confidence: 99%

Closing the Gap on Autosomal Dominant Connexin-26 and Connexin-43 Mutants Linked to Human Disease

Laird

2008

Journal of Biological Chemistry

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Cells within the vast majority of human tissues communicate directly through clustered arrays of intercellular channels called gap junctions. Gene ablation studies in mouse models have revealed that these intercellular channels are necessary for a variety of organ functions and that some of these genes are essential for survival. Molecular genetics has uncovered that germ line mutations in nearly half of the genes that encode the 21-member connexin family of gap junction proteins are linked to one or more human diseases. Frequently, these mutations are autosomal recessive, whereas in other cases, autosomal dominant mutations manifest as disease. Given the broad and overlapping distribution of connexins in a wide arrangement of tissues, it is hard to predict where connexin-linked diseases will clinically manifest. For instance, the most prevalent connexin in the human body is connexin-43 (Cx43), yet autosomal dominant mutations in the GJA1 gene, which encodes Cx43, exhibit modest developmental disorders resulting in a disease termed oculodentodigital dysplasia. Autosomal recessive mutations in the gene encoding Cx26 result in moderate to severe sensorineural hearing loss, whereas autosomal dominant mutations produce hearing loss and a wide range of skin diseases, including palmoplantar keratoderma. Here, we will focus on autosomal dominant mutations of the genes encoding Cx26 and Cx43 in relation to models that link genotypes to phenotypic outcomes with particular reference to how these approaches provide insight into human disease.

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“…3). Interestingly, except for the two mutations mentioned above [146,150] [103] in a family with ODDD and an increased incidence of cardiac arrhythmias. Cx43 was markedly reduced in mutant hearts with preferential loss of phosphorylated forms of the protein, resulting in dysfunctional GJs.…”

Section: Cx43 and Oculodentodigital Dysplasiamentioning

confidence: 93%

“…The authors stated that this was the first reported mutation affecting the COOH-terminal tail and suggested that this particular mutation might explain the presence of skin symptoms. Vreeburg et al [150] reported another Dutch woman with ODDD and palmar hyperkeratosis with a 2-bp deletion in the Cx43 gene resulting in truncation of the protein and absence of a significant portion of the C-terminal domain. The findings suggested a genotype/ phenotype correlation between pronounced PPK and mutations that truncate the C terminus of Cx43.…”

Section: Cx43 and Oculodentodigital Dysplasiamentioning

confidence: 98%

Gap junctions in inherited human disease

Zoidl

Dermietzel

2010

Pflugers Arch - Eur J Physiol

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Gap junctions (GJ) provide direct intercellular communication. The structures underlying these cell junctions are membrane-associated channels composed of six integral membrane connexin (Cx) proteins, which can form communicating channels connecting the cytoplasms of adjacent cells. This provides coupled cells with a direct pathway for sharing ions, nutrients, or small metabolites to establish electrical coupling or balancing metabolites in various tissues. Genetic approaches have uncovered a still growing number of mutations in Cxs related to human diseases including deafness, skin disease, peripheral and central neuropathies, cataracts, or cardiovascular dysfunctions. The discovery of a growing number of inherited human disorders provides an unequivocal demonstration that gap junctional communication is crucial for diverse physiological processes.

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Skin changes in oculo‐dento‐digital dysplasia are correlated with C‐terminal truncations of connexin 43

Cited by 56 publications

References 7 publications

Caveolin-1 and -2 Interact with Connexin43 and Regulate Gap Junctional Intercellular Communication in Keratinocytes

Caveolin-1 and -2 Interact with Connexin43 and Regulate Gap Junctional Intercellular Communication in Keratinocytes

Closing the Gap on Autosomal Dominant Connexin-26 and Connexin-43 Mutants Linked to Human Disease

Gap junctions in inherited human disease

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