Gudmundsson Sanna, Wilbe Maria, Ekvall Sara, Ameur Adam, Cahill Nicola, Alexandrov Ludmil B, Virtanen Marie, Hellström Pigg Maritta, Vahlquist Anders, Törmä Hans, Bondeson Marie-Louise
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, NM, USA and.
Hum Mol Genet. 2017 Mar 15;26(6):1070-1077. doi: 10.1093/hmg/ddx017.
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.
回复性镶嵌现象（RM）是一种自然发生的现象，即种系突变的致病效应通过第二次体细胞事件得到纠正。在患有各种遗传性皮肤病的患者中已观察到由于RM导致的外观健康的皮肤发育，但在与连接蛋白相关的疾病中未观察到。我们旨在阐明一名患有角膜炎-鱼鳞病-耳聋（KID）综合征患者皮肤中疑似RM的潜在分子机制。该患者因特征性皮肤病变、听力缺陷和角膜炎被诊断为KID综合征。对编码连接蛋白（Cx）26的GJB2进行调查发现，其存在复发性新生种系突变c.148G＞A，p.Asp50Asn的杂合性。在20岁时，该患者出现了外观健康的皮肤斑点，这些斑点在广泛的红皮病性角化过度病变中大小和数量不断增加。对两份外观健康的皮肤活检样本进行超深度测序，确定了五个体细胞非同义突变，它们独立地与p.Asp50Asn突变呈顺式存在。在HeLa细胞中对Cx26进行功能研究发现，Cx26-Asp50Asn和野生型Cx26在间隙连接通道斑块中共表达。然而，带有在患者中鉴定出的第二位点突变的Cx26-Asp50Asn未形成间隙连接通道斑块。我们认为，第二位点突变独立抑制了间隙连接通道中Cx26-Asp50Asn的表达，从而逆转了p.Asp50Asn突变的显性负效应。据我们所知，这是首次报道RM导致KID综合征患者出现外观健康的皮肤。
