Abstract
Revertant mosaicism (RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c.148G > A, p.Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultra-deep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p.Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p.Asp50Asn mutation. To our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.
Highlights
Keratitis-ichthyosis-deafness (KID) syndrome (OMIM #148210) is a rare congenital ectodermal disorder characterized by keratitis, sensorineural hearing loss, and ichthyosis/erythrokeratoderma that manifests as patches of red, thickened, scaly, and dry skin [1]
At 30 years of age, she developed invasive squamous cell carcinoma (SCC) on her left thigh (Fig. 2F), which was surgically removed with no signs of spreading
This study is the first one, to our knowledge, to describe Revertant mosaicism (RM) that resulted in the development of healthy-looking skin in a patient with KID syndrome
Summary
Keratitis-ichthyosis-deafness (KID) syndrome (OMIM #148210) is a rare congenital ectodermal disorder characterized by keratitis, sensorineural hearing loss, and ichthyosis/erythrokeratoderma that manifests as patches of red, thickened, scaly, and dry skin [1]. Nine mutations [3] in Cx26 have been reported to cause KID syndrome in altogether approximately 100 cases [4]. The diseases-phenotype has been demonstrated in a mouse model expressing the GJB2 c.50C > T, p.Ser17Phe mutation, a mutation reported to cause KID syndrome in humans [10]. Mutations in GJB2 are associated with a number of other diseases, including Vohwinkel syndrome (OMIM #124500), Bart–Pumphrey syndrome (OMIM #149200), syndromic sensorineural hearing loss with keratoderma (OMIM #148350), hystrix-like ichthyosis-deafness syndrome (OMIM #602540), and nonsyndromic deafness (OMIM #601544, #220290)
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