Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Life Sci Alliance. 2019 Feb 4;2(1). doi: 10.26508/lsa.201800284. Print 2019 Feb.
Revertant mosaicism is a phenomenon in which pathogenic mutations are rescued by somatic events, representing a form of natural gene therapy. Here, we report on the first evidence for revertant mosaicism in loricrin keratoderma (LK), an autosomal dominant form of ichthyosis caused by mutations in on 1q21.3. We identified two unrelated LK families exhibiting dozens of previously unreported white spots, which increased in both number and size with age. Biopsies of these spots revealed that they had normal histology and that causal mutations were lost. Notably, dense single nucleotide polymorphism mapping identified independent copy-neutral loss-of-heterozygosity events on chromosome 1q extending from regions centromeric to to the telomere in all investigated spots, suggesting that somatic recombination represents a common reversion mechanism in LK. Furthermore, we demonstrated that reversion of mutations confers a growth advantage to cells in vitro, but the clinically limited size of revertant spots suggests the existence of mechanisms constraining revertant clone expansion. Nevertheless, the identification of revertant mosaicism in LK might pave the way for revertant therapy for this intractable disease.
回复性嵌合体是一种由体细胞事件挽救致病性突变的现象，代表了一种自然基因治疗形式。在这里，我们报告了角蛋白鱼鳞病（LK）中回复性嵌合体的第一个证据，这是一种常染色体显性遗传的鱼鳞病，由 1q21.3 上的 突变引起。我们鉴定了两个不相关的 LK 家族，这些家族表现出数十个以前未报道过的白点，其数量和大小随着年龄的增长而增加。这些斑点的活检显示它们具有正常的组织学，并且因果关系 突变丢失了。值得注意的是，密集的单核苷酸多态性图谱在所有研究的斑点中发现了独立的染色体 1q 上的拷贝中性杂合性丢失事件，从着丝粒区域延伸到端粒区域，表明体细胞重组是 LK 中常见的回复机制。此外，我们证明了 突变的回复赋予了细胞在体外的生长优势，但临床上有限的回复性斑点大小表明存在限制回复性克隆扩展的机制。然而，LK 中回复性嵌合体的鉴定可能为这种棘手疾病的回复性治疗铺平道路。
