SASH1 has been reported as a causal gene of lentiginous phenotypes with and without heredity, including an autosomal dominant type characterized by lentigines predominantly on sun‐exposed areas such as the face and limbs. Recently, cases of dyschromatosis with SASH1 mutations have been reported worldwide; however, only one case has been reported from Japan. Here, we analyzed six Japanese patients who characteristically showed many lentigines on sun‐exposed areas, using next‐generation sequencing. We identified five novel heterozygous mutations in SASH1 (p.I586M, p.S531Y, p.R644W, p.T525R, and p.S516I) in our patients and their families. The p.R644W substitution identified in two unrelated families was the first mutation located in the sterile alpha motif 1 (SAM1) domain. The degree and location of the lentigines were variable across individuals, even if they shared the same SASH1 mutation. All mutations were predicted to be deleterious by six different algorithms used to evaluate the functional impact of a variation. In addition, immunohistopathological findings and RNA sequencing results suggested that SASH1 mutations were associated with an increase in the number of melanocytes, acceleration of melanogenesis, and upregulated hair keratin expression.

中文翻译：

---

SASH1 中的五个新突变导致日本家庭的长斑表型

SASH1已被报道为具有和不具有遗传性的雀斑表型的致病基因，包括常染色体显性遗传类型，其特征是雀斑主要出现在暴露在阳光下的区域，如面部和四肢。最近，世界范围内报道了伴有SASH1突变的色觉障碍病例；然而，日本仅报告了一例。在这里，我们使用新一代测序分析了 6 名日本患者，这些患者的特征是在阳光照射区域出现许多雀斑。我们在SASH1 中发现了五个新的杂合突变（p.I586M、p.S531Y、p.R644W、p.T525R 和 p.S516I）在我们的患者及其家属中。在两个不相关的家族中发现的 p.R644W 取代是位于不育 alpha 基序 1 (SAM1) 域中的第一个突变。扁豆的程度和位置因人而异，即使它们共享相同的SASH1突变。通过用于评估变异的功能影响的六种不同算法，预测所有突变都是有害的。此外，免疫组织病理学发现和 RNA 测序结果表明，SASH1突变与黑色素细胞数量增加、黑色素生成加速和毛发角蛋白表达上调有关。