The PER3rs772027021 SNP induces pigmentation phenotypes of dyschromatosis universalis hereditaria

Abstract

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^rs772027021 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^rs772027021 SNP in this family demonstrated mild-pigmented phenotypes compared to those of the proband carrying PER3^rs772027021 SNP and SASH1 ^T525R mutation. Increased melanin synthesis was induced by PER3^rs772027021 SNP in the melanocytes of affected epithelial tissues. Mutated SASH1 or PER3^rs772027021 SNP alone or cooperation of mutation of SASH1 and PER3^rs772027021 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^rs772027021 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. SASH1^T525R mutation is confirmed to associate with DUH. A novel autosomal dominant inheritance DUH subtype with mild pigmentated phenotypes is caused by the PER3^rs772027021 SNP.

Keywords: Dyschromatosis universalis hereditaria (DUH); Hyperpigmentation phenotype; PER3 SNP; SASH1 mutation.