Sporadic Dyschromatosis Universalis Hereditaria: A Second Case Report From Iran

et al. 2023

J Mol Med

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 identi ed 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 fourgeneration 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 zebra sh mutant line harboring the PER3 rs772027021 SNP to induce melanocyte proliferation in vivo . Our results are the rst 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.

Section: Clinical Featuresmentioning

confidence: 80%

The PER3rs772027021 SNP induces pigmentation phenotypes of dyschromatosis universalis hereditaria

et al. 2023

J Mol Med

“…Mosaic-like melanin distribution in basal and horny layers in the hyperpigmented macules also appeared in the affected epithelial layers of PER3 rs772027021 SNP DUH In general, DUH should be considered in the differential diagnosis of all cases manifesting as mixed hyper and hypopigmented macules, and biopsy specimens should be obtained to confirm the diagnosis 22. Phenotypes of increased melanin pigmentation were demonstrated in the affected skin epithelial tissues of two affected individuals and the proband of this PER3 rs772027021 SNP-related DUH family using melanin staining.…”

mentioning

confidence: 99%

Retyping and molecular pathology diagnosis of dyschromatosis universalis hereditaria

Zhou

Experimental Dermatology

2023

Dyschromatosis universalis hereditaria (DUH) is characterized by diffuse symmetrically distributed hypopigmented macules mixed with hyperpigmentation. DUH is divided into three types by Online Mendelian inheritance in man (OMIM) that is, DUH1 (OMIM 127500), DUH2 (OMIM 612715) and DUH3 (OMIM 615402) according to the different linkage regions. Although each condition possesses corresponding phenotypic characteristics and the prognosis for each is somewhat different, these disorders are highly overlapped and difficult to differentiate in the clinical setting. Our latest study reveals a novel DUH subtype that presents a mild phenotype of pigmentation anomalies and is named PER3rs772027021 SNP related DUH or DUH4 by us, which make the DUH subtype can be further retyped. Heterozygous distribution or mosaic‐like distribution of melanin is a newly discovered pathological features that is uniquely demonstrated in the affected layers of DUH1 and DUH4 patients. In this review, DUH is further divided into four subtypes according the causative genes and their mutational sites, and the mutation regions described in the previous reports. To make an accurate diagnosis, we suggest that Sanger sequencing or the target region sequencing (TRS) to the candidate causative genes related melanogenesis may be the most effective and convenient method of clinical diagnosis or/and prenatal diagnosis for DUH and DUH‐like patients. More importantly, heterozygous distribution or mosaic‐like distribution of melanin can be utilized for differential diagnosis of DUH. We also investigate the underlying molecular mechanism to form mosaic‐like melanin in the affected layers of hyper‐ and/or hypo‐pigmented macules from DUH1 and DUH4 patients. This review provides a molecular and pathological delineation of four types of DUH and aims to establish a concise diagnostic strategy to allow clinical dermatologists to make an accurate diagnosis.

The PER3 rs772027021 SNP induces pigmentation phenotypes of dyschromatosis universalis hereditaria

et al. 2022

Preprint

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.