Japanese case of oculodentodigital dysplasia caused by a mutation in the GJA1 gene

Dear Editor, Oculodentodigital Dysplasia (ODDD; Online Mendelian Inheritance in Man no. 164200) is a rare condition characterized by ocular symptoms, enamel hypoplasia, long and narrow nose, and syndactyly type III, which are common clinical features across different populations.1-3 In some cases, affected individuals can show a variety of cutaneous and neurological manifestations.1-3 ODDD typically shows an autosomal dominant inheritance trait, while sporadic cases also frequently exist.1 The causative gene GJA1 encodes connexin 43 (Cx43), which is a 4-pass transmembrane protein and is a major component of gap junctions.1 To date, many cases of ODDD have been reported in the published work, but information of the disease in a Japanese population is still limited.2, 3 We herein report a Japanese patient with ODDD resulting from a GJA1 mutation. A 4-year-old Japanese boy visited Kobe university hospital due to sparse scalp hair. He had various additional symptoms including narrow nose, low-set ear, strabismus, glaucoma, macular hypoplasia of retina, brittle nails of fingers and toes, brachydactyly, and past surgical history of left fourth–fifth finger syndactyly (Fig. 1a–c). He also showed enamel hypoplasia and hypodontia (data not shown), while neurological abnormalities or palmoplantar keratoderma were not evident. Both parents were unaffected and there were no consanguinities between them. Most of these clinical findings were consistent with ODDD. Following written informed consent, we isolated genomic DNA from blood samples of the patient and his mother (under institutional approval and adhering to the principles of the Declaration of Helsinki). His father's DNA was unavailable. Direct sequencing analysis of the GJA1 gene was performed as described previously.1 We identified a heterozygous missense mutation c.119C>T (p.Ala40Val) in the GJA1 gene of the patient, but not of his mother (Fig. 1d). The results were confirmed by screening assay with the restriction enzyme TspRI (Fig. 1e). Although we were unable to analyze the patient's father, we postulated that the nucleotide substitution c.119C>T in GJA1 was most likely a de novo mutation that had occurred in the patient's somatic cells or germ cells of either parent. The GJA1 mutation that we detected in our patient was previously identified in a sporadic case of ODDD in another population thus turned out to be recurrent.1 The c.119C>T change occurred in CpG dinucleotide sequences in which nucleotide substitutions were prone to be introduced, suggesting that this position is a mutational hot spot in the GJA1 gene. Cx43 is abundantly expressed in the epidermis and skin appendages.4 The crucial roles of Cx43 in cutaneous development are supported by the evidence that ODDD can show various skin symptoms, such as hypotrichosis, brittle nails and palmoplantar keratoderma,1 although it remains unknown how GJA1 mutations caused these phenotypes. The missense mutation p.Ala40Val is located in the first transmembrane domain of Cx43. Importantly, it has previously been demonstrated that the p.Ala40Val mutant Cx43 protein was able to form gap junction plaques, but lost its channel function in vitro.5 However, because the mutation p.Ala40Val was identified in a heterozygous state, further studies will be required to investigate whether the mutant Cx43 shows a dominant negative effect against wild-type Cx43. This study was supported in part by a grant from Takeda Science Foundation, Japan (to Y. S.), and by the "Research on Measures for Intractable Diseases" Project: matching fund subsidy (H26-077) from the Ministry of Health, Labor and Welfare, Japan. None declared.