Cell–cell communication mediated by gap junctions, consisting of connexins, is a crucial function of all cells in multicellular organisms to maintain tissue homeostasis, synchronize their response, and control growth and development. Erythrokeratodermia variabilis (EKV; Online Mendelian Inheritance in Man no. 133200) is an autosomal dominant or recessive genodermatosis characterized by the coexistence of transient erythematous patches and fixed hyperkeratotic plaques. EKV is caused by pathogenic mutations in connexin genes, GJB3 and GJB4 coding for the connexin proteins Cx31 and Cx30.3, respectively. Here, we describe a Japanese case of EKV documented for the first time to have a missense mutation in GJB3 and confirmed the low expression of Cx31 in the patient's epidermal keratinocytes.
A 2-year-old Japanese girl presented with a generalized erythematous eruption. The patient developed erythematous lesions on her cheeks at birth, which extended to other body sites at the age of 3 months. She was born to non-consanguineous, unaffected parents. On examination, she had asymptomatic, irregularly shaped, sharply demarcated, erythematous patches on her cheeks, trunk (Fig. 1a) and four extremities (Fig. 1b). These lesions were transient, but reappeared repeatedly. Persistent indurated erythematous plaques were also found on the lower limbs (Fig. 1b). Her palms and soles were remarkably hyperkeratotic (Fig. 1c). Her whole body was covered with fine scales. Histopathological examination obtained from a calf plaque showed hyperkeratosis and papillomatosis, representing the “church spire” configuration (Fig. 2a). A mild dermal lymphocytic infiltrate was observed. Gene analysis of her blood cells disclosed a heterozygous G→C transition at nucleotide 125 (c.125G>C) of GJB3, leading to the substitution of arginine 42 by proline (R42P). No mutation was found in GJB4. Deparaffinized sections of the biopsy specimen were immunohistochemically stained for Cx31. A specimen from the same site of a normal individual of the same age was used as control. Positive intercellular staining was found in the upper half of the epidermis of the normal skin (Fig. 2b). However, the patient's skin showed no intercellular staining for Cx31, although it exhibited a cytoplasmic expression pattern of Cx31 (Fig. 2c). The patient was treated with topical emollients, keratolytics and corticosteroids with limited improvement. Her parents did not consent to gene analysis.
Several mutations in GJB3 and GJB4 have been found mainly in the European patients with EKV. Nakamura et al. summarized the features of four Japanese EKV patients investigated genetically and proposed the possible ethnic differences in the pathogenesis between the Japanese and other cases. The female sex and the lack of family history seen in our patient are consistent with the characteristics of the reported Japanese cases. While GJB3 or GJB4 mutations were not identified in the reported Japanese cases, we found a GJB3 missense mutation in our case. This is the first document of GJB3 mutation-bearing Japanese case. GJB3 R42P was previously reported in one family and a de novo case in other countries. The mutation replaces a positively charged residue with a non-polar residue. This change may alter the conformation of the protein and voltage gating polarity leading to impaired gap junctional intercellular communication (GJIC).
We found lack of intercellular staining for Cx31 in our case, which is consistent with the previous observation. It is suggested that the mutant proteins are not correctly trafficked to cell membrane. Because the Cx31 is a major connexin protein in the epidermis, such a failure in the trafficking may also contribute to the GJIC of the skin. The EKV eruptions can be triggered by environmental stresses, such as temperature change, mechanical irritation and sun exposure to the skin. It is tempting to speculate that attenuation of transfer of small molecules, such as inositol triphosphate and calcium as a consequence of the impaired GJIC, leads to the vulnerability to such stresses and the resultant occurrence of the eruptions.