Mutated SASH1 promotes Mitf expression in a heterozygous mutated SASH1 knock‑in mouse model

Abstract

The SAM and SH3 domain-containing 1 (SASH1) genes have been identified as the causal genes of dyschromatosis universalis hereditaria (DUH); these genes cause the pathological phenotypes of DUH, and SASH1 variants have been shown to regulate the abnormal pigmentation phenotype in human skin in various genodermatoses. However, investigations into the mutated SASH1 gene have been limited to in vitro studies. In the present study, to recapitulate the molecular pathological phenotypes of individuals with DUH induced by SASH1 mutations, a heterozygous BALB/c mouse model, in which the human SASH1 c.1654 T>G (p. Tyr 551Asp, Y551D) mutation was knocked in was first generated. The in vivo functional experiments on Y551D SASH1 indicated that the increased expression of microphthalmia-associated transcription factor (Mitf) was uniformly induced in the tails of heterozygous BALB/c mice, and an increased quantity of Mitf-positive epithelial cells was also detected. An increased expression of Mitf-and Mitf-positive cells was also demonstrated in the epithelial tissues of Y551D-SASH1 affected individuals. In the present study, Mitf expression was also found to be increased by Y551D SASH1 in vitro. Taken together, these findings indicate that the upregulation of Mitf is the bona fide effector of the Y551D SASH1-mediated melanogenesis signaling pathway in vivo. SASH1 may function as a scaffold molecule for the assembly of a SASH1-Mitf molecular complex to regulate Mitf expression in the cell nucleus and thus to promote the hyperpigmented phenotype in the pathogenesis of DUH and other genodermatoses related to pigment abnormalities.

Novel missense mutation of SASH1 in a Chinese family with dyschromatosis universalis hereditaria

“…Recently, in vivo studies on SASH1 function were investigated in a heterozygous mouse model in which the SASH1 c.1654T>G (p.Tyr551Asp, Y551D) mutation was knocked in. Xu et al pointed out that SASH1 regulates the expression of Mitf in the nucleus by acting as a scaffold molecule that participates in the assembly of the SASH1-MITF molecular complex and promotes the hyperpigmentation phenotype in the pathogenesis of DUH and other dermatoses related to abnormal pigmentation [ 10 ].…”

The emerging and diverse roles of the SLy/SASH1‐protein family in health and disease—Overview of three multifunctional proteins

“…The authors conclude that SASH1 might induce accumulation of the transcription factor MITF in the nucleus, to regulate the signaling pathway of melanogenesis in vivo and in vitro. 139 Unpublished observations from our group indicate a central role of SASH1 in pigmentation in mouse models and human melanoma cells, although no altered migratory behavior of melanocytes could be detected. In addition, a recent investigation of six Japanese patients with lentigines identified five novel heterozygous mutations in the SASH1 locus by using next-generation sequencing.…”

“…This mutation is known to cause DUH in humans and was inserted into fertilized oocytes using a murine SASH1 vector under the control of its promoter. The authors conclude that SASH1 might induce accumulation of the transcription factor MITF in the nucleus, to regulate the signaling pathway of melanogenesis in vivo and in vitro 139 . Unpublished observations from our group indicate a central role of SASH1 in pigmentation in mouse models and human melanoma cells, although no altered migratory behavior of melanocytes could be detected.…”

The PER3rs772027021 SNP induces pigmentation phenotypes of dyschromatosis universalis hereditaria

“…SASH1 is a signaling adaptor protein of 1,247 amino acids that contains an evolutionarily conserved SLY domain (401-555), an SH3 domain (557-614) and two SAM domains (633-697 and 1177-1241, annotation from the UniProt database) [34]. Increasing numbers of SASH1 variants have been found to be associated with DUH [7-11, 13, 14].…”

“…Melanin staining in the skin epithelial tissues of healthy controls and affected individuals in the DUH family was performed as previously described [7,34].…”