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

Journal Article · Wed Feb 01 00:00:00 EST 2017 · Human Molecular Genetics

DOI:https://doi.org/10.1093/hmg/ddx017· OSTI ID:1351191

Gudmundsson, Sanna ^[1]; Wilbe, Maria ^[1]; Ekvall, Sara ^[1]; Ameur, Adam ^[1]; Cahill, Nicola ^[1]; Alexandrov, Ludmil B.  ^[2]; Virtanen, Marie ^[1]; Hellström Pigg, Maritta ^[1]; Vahlquist, Anders ^[1]; Törmä, Hans ^[1]; Bondeson, Marie -Louise ^[1]

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1. Uppsala Univ., Uppsala (Sweden)
2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

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. Finally 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.

• Research Organization: Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
• Sponsoring Organization: USDOE Laboratory Directed Research and Development (LDRD) Program
• Grant/Contract Number: AC52-06NA25396
• OSTI ID: 1351191
• Report Number(s): LA-UR-16-23164
• Journal Information: Human Molecular Genetics, Vol. 26, Issue 6; ISSN 0964-6906
• Publisher: Oxford University Press
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
Biological Science