The PER3rs772027021 SNP induces pigmentation phenotypes of dyschromatosis universalis hereditaria

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 (PER3rs772027021 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 PER3rs772027021 SNP in this family demonstrated mild-pigmented phenotypes compared to those of the proband carrying PER3rs772027021 SNP and SASH1 T525R mutation. Increased melanin synthesis was induced by PER3rs772027021 SNP in the melanocytes of affected epithelial tissues. Mutated SASH1 or PER3rs772027021 SNP alone or cooperation of mutation of SASH1 and PER3rs772027021 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 PER3rs772027021 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 rs772027021 SNP is identified to be associated with hyperpigmentation and/or hypopigmentation phenotype and the novel pathogenic variant of PER3 rs772027021 SNP probably contributed the pathogenesis of DUH. SASH1T525R mutation is confirmed to associate with DUH. A novel autosomal dominant inheritance DUH subtype with mild pigmentated phenotypes is caused by the PER3rs772027021 SNP.