Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26.

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Gudmundsson S, Wilbe M, Ekvall S, Ameur A, Cahill N, Alexandrov LB, Virtanen M, Hellström Pigg M, Vahlquist A, Törmä H, Bondeson ML

Hum. Mol. Genet. 26 (6) 1070-1077 [2017-03-15; online 2017-02-06]

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.

Affinity Proteomics Uppsala [Collaborative]

Bioinformatics Support for Computational Resources [Service]

Clinical Genomics Uppsala [Collaborative]

NGI Uppsala (Uppsala Genome Center) [Collaborative]

National Genomics Infrastructure [Collaborative]

PLA and Single Cell Proteomics [Service]

PubMed 28158657

DOI 10.1093/hmg/ddx017

Crossref 10.1093/hmg/ddx017

pii: 2965926
pmc: PMC5409067