PER3 rs772027021 SNP  induce 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 motifs- and SH3 domain-containing protein 1 (SASH1) and ATP-binding cassette subfamily B, member 6(ABCB6) have been identified as the causative genes for this disorder, there are still some cases with unknown pathogenic genes. In this study, whole exome sequencing, data analysis and sanger sequencing were utilized in a four-generations extended Chinese family with DUH. A single nucleotide polymorphism (SNP) (c. 517C > T (p.P173S, rs772027021) variant in the exon 5 of Period Circadian Regulator 3 (PER3) (NM_001289861), was found in each affected individuals of the DUH family and the c. 517C > T SNP of PER3( PER3 rs772027021 SNP) and a novel c. 1574C > G (p.T525R) mutation in exon 14 of SASH1 were both found in the proband. Increased melanin syntheses were induced by the PER3 rs772027021 SNP in melanocytes of the affected epithelial tissues. Mutated SASH1 or PER3 rs772027021 SNP alone, or mutated SASH1 and PER3 rs772027021 SNP synergistically caused more synthesized melanin, respectively in vitro. We also phenotypically characterized a commercially available zebrafish mutant line that harbored PER3 rs772027021 SNP to induce proliferative melanocytes in vivo. Our studies firstly revealed the PER3 SNP may be as the pathogenic gene for a novel DUH subtype which was of delayed dominance and mutation of SASH1 and PER3 cooperatively promote hyperpigmentation phenotypes.