SASH1 promotes melanin synthesis and migration via suppression of TGF-β1 secretion in melanocytes resulting in pathologic hyperpigmentation

Abstract

Dyschromatosis universalis hereditaria (DUH) is an autosomal dominant pigmentary genodermatosis characterized by the presence of patches of hyperpigmentation and hypopigmented macules distributed over the body, with most cases reported in Asia. DUH is a heterogeneous disease and a small portion of patients carry the ABCB6 variant. In the present study, exome sequencing of four generations of a Chinese family with DUH identified a c.1761C>G (p.Ser587Arg) mutation in exon 15 of SAM and SH3 domain containing 1 (SASH1) that was found to co-segregate in some family members. Immunohistological analysis of biopsy specimens showed that SASH1 was diffusely distributed in all layers of the epidermis, suggesting increased transepithelial migration of melanocytes (MCs). The point mutation c.1761C>G of SASH1 was successfully induced in immortalized human melanocyte (PIG1) cells, which resulted in the downregulation of SASH1 expression. Bioinformatics analysis showed that mutated SASH1 downregulated thrombospondin 1 (THBS1) expression and inactivated transforming growth factor beta 1 (TGF-β1) signaling. TGF-β1 expression by PIG1cells was found to negatively regulate SASH1 protein expression. Transwell migration and wound-healing assays showed an increase in the migration and invasion capabilities of the cells carrying the mutation. Further, SASH1 mutations induced downregulation of melanin content. The study results suggest cross-talking between SASH1-TGF-β1 signaling, demonstrating the proposed MC migration modulation models and affecting melanin trafficking in the epithelium.

Identification of a Novel Mutation in SASH1 Gene in a Chinese Family With Dyschromatosis Universalis Hereditaria and Genotype-Phenotype Correlation Analysis

“…Only one affected individual manifested as generalized reticulate hypopigmented macules. Most recently, this missense mutation (c.1761C > G, p.S587R) has also been identified in a large Chinese family with four generation (Cui et al, 2020). Zhong et al (2019a) described two unrelated DUH families carrying mutations in SASH1.…”

Five novel mutations in SASH1 contribute to lentiginous phenotypes in Japanese families

“…Among the five novel SASH1 mutations, three (p.S531Y, p.T525R, and p.S516I) were localized to the SLY domain that may represent a potential mutational hotspot (Wang et al., 2017; Zhang et al., 2016) (Figure 1l). The p.I586M substitution was localized to the SH3 domain which was also a causative region for this phenotype (Cui et al., 2020; Zhong et al., 2019) (Figure 1l). The p.R644W substitution was the first mutation localized to the SAM1 domain of the SASH1 (Figure 1l).…”

“…However, details regarding pathological conditions and classification remain poorly understood. Recently, several families with new pigmentation disorders caused by mutations in the SAM (sterile alpha motif) and SH3 (Src homology domain 3) domain‐containing protein 1 (SASH1) gene have been reported worldwide, especially in China (Courcet et al., 2015; Cui et al., 2020; Shellman et al., 2015; Wang et al., 2017; Zhang et al., 2016; Zhong et al., 2019; Zhou et al., 2013). SASH1 , located on chromosome 6q24.3, which is composed of 20 exons, is part of the SLY (SH3 domain‐containing protein expressed in lymphocytes) family of signal adapter proteins (Zeller et al., 2003).…”

“…Moreover, these mutations promote melanogenesis by upregulating the p53‐POMC‐MC1R cascade through UV exposure (Zhou et al., 2017). The p.S587R mutation promotes downregulation of SASH1 expression, melanogenesis, and upregulation of migration through the suppression of TGF‐β1 secretion in human cultured melanocyte cells (Cui et al., 2020).…”

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

“…92,93 Another mechanism described propagates the inactivation of TGF-β1 via the downregulation of THSB1 due to mutated SASH1 resulting in altered melanocyte migration and melanin synthesis in PIG1 cells. 138 In addition, an in vivo approach tried to investigate the function of SASH1 in melanogenesis by expressing a known human point mutation in the SASH1 gene (Y551D) in BALB/cJ mice. 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.…”