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

Abstract

Oculo-dento-digital dysplasia (ODDD, OMIM no.164210) is a pleiotropic disorder caused by mutations in the GJA1 gene that codes for the gap junction protein connexin 43. While the gene is highly expressed in skin, ODDD is usually not associated with skin symptoms. We recently described a family with ODDD and palmoplantar keratoderma. Interestingly, mutation carriers had a novel dinucleotide deletion in the GJA1 gene that resulted in truncation of part of the C-terminus. We speculated, that truncation of the C-terminus may be uniquely associated with skin disease in ODDD. Here, we describe a patient with ODDD and palmar hyperkeratosis caused by a novel dinucleotide deletion that truncates most of the connexin 43 C-terminus. Thus, our findings support the notion that such mutations are associated with the occurrence of skin symptoms in ODDD and provide the first evidence for the existence of a genotype-phenotype correlation.

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

“…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.…”

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

“…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.…”

“…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.…”

Gap junctions in inherited human disease

“…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.…”

“…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.…”