Chen Hongyu, Yang Pingping, Yang Dan, Wang Dongsheng, Lu Mao, Li Yadong, Zhong Zhiqiang, Zhang Jing, Zeng Zhen, Liu Zhi, Zeng Xiaohua, Jia Xu, Xing Qinghe, Zhou Ding'an
School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou, 550004, People's Republic of China.
Clinical Research Center, the Affiliated Hospital of Guizhou Medical University, No.9 Beijing Road, Guiyang, Guizhou, 550004, People's Republic of China.
J Mol Med (Berl). 2023 Mar;101(3):279-294. doi: 10.1007/s00109-023-02288-6. Epub 2023 Feb 15.
Dyschromatosis universalis hereditaria (DUH) is a pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules distributed randomly over the body. Although Sterile Alpha motif- and SH3 domain-containing protein 1 (SASH1) and ATP-binding cassette subfamily B, member 6 (ABCB6) have been identified as causative genes for this disorder, some cases involve unknown pathogenic genes. In this study, whole-exome sequencing, data analysis, and Sanger sequencing were utilized for a four-generation extended Chinese family with DUH. A single-nucleotide polymorphism (SNP) (c. 517C > T (p.P173S), rs772027021) variant in exon 5 of Period Circadian Regulator 3 (PER3) (NM_001289861) was detected in each affected individual of the DUH family; the c. 517C > T SNP of PER3 (PER3 SNP) and a novel mutation in exon 14 of SASH1 (c. 1574C > G (p.T525R)) were both found in the proband. The affected individuals carrying PER3 SNP in this family demonstrated mild-pigmented phenotypes compared to those of the proband carrying PER3 SNP and SASH1 mutation. Increased melanin synthesis was induced by PER3 SNP in the melanocytes of affected epithelial tissues. Mutated SASH1 or PER3 SNP alone or cooperation of mutation of SASH1 and PER3 SNP synergistically led to increased melanin synthesis and enhanced proliferation of melanoma cells in vitro. We also phenotypically characterized a commercially available zebrafish mutant line harboring the PER3 SNP to induce melanocyte proliferation in vivo. Our results are the first to reveal that this PER3 SNP may be pathogenic for a novel DUH subtype with mild hyperpigmented and/or hypopigmented phenotypes and that mutation of SASH1 and PER3 cooperatively promotes hyperpigmentation phenotypes. KEY MESSAGES: PER3 SNP is identified to be associated with hyperpigmentation and/or hypopigmentation phenotype and the novel pathogenic variant of PER3 SNP probably contributed the pathogenesis of DUH. SASH1 mutation is confirmed to associate with DUH. A novel autosomal dominant inheritance DUH subtype with mild pigmentated phenotypes is caused by the PER3 SNP.
泛发性遗传性色素沉着异常（DUH）是一种色素性基因皮肤病，其特征是色素沉着过度和色素沉着不足的斑片混合，随机分布于全身。尽管含无菌α基序和SH3结构域蛋白1（SASH1）和ATP结合盒亚家族B成员6（ABCB6）已被确定为该疾病的致病基因，但仍有一些病例涉及未知的致病基因。在本研究中，对一个四代扩展的中国DUH家族进行了全外显子测序、数据分析和桑格测序。在DUH家族的每个患病个体中检测到周期昼夜调节因子3（PER3）（NM_001289861）第5外显子中的一个单核苷酸多态性（SNP）（c.517C＞T（p.P173S），rs772027021）变异；先证者中同时发现了PER3的c.517C＞T SNP（PER3 SNP）和SASH1第14外显子中的一个新突变（c.1574C＞G（p.T525R））。与携带PER3 SNP和SASH1突变的先证者相比，该家族中携带PER3 SNP的患病个体表现出色素沉着较轻的表型。PER3 SNP可诱导受累上皮组织黑素细胞中黑色素合成增加。单独的SASH1突变或PER3 SNP，或SASH1与PER3 SNP突变协同作用，均可导致体外黑色素瘤细胞黑色素合成增加和增殖增强。我们还对携带PER3 SNP的市售斑马鱼突变品系进行了表型特征分析，以诱导体内黑素细胞增殖。我们的结果首次揭示，这种PER3 SNP可能是一种具有轻度色素沉着过度和/或色素沉着不足表型的新型DUH亚型的致病因素，并且SASH1和PER3的突变协同促进色素沉着过度表型。关键信息：PER3 SNP被确定与色素沉着过度和/或色素沉着不足表型相关，PER3 SNP的新型致病变异可能导致DUH的发病机制。SASH1突变被证实与DUH相关。PER3 SNP导致一种具有轻度色素沉着表型的新型常染色体显性遗传DUH亚型。
