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

Xu,Zexi; Xu,Zexi; Li,Yadong; Li,Yadong; Wang,Dahong; Wang,Dahong; Wu,Daoqiu; Wu,Daoqiu; Wang,Jinyun; Wang,Jinyun; Chen,Lian; Chen,Lian; Deng,Yinqian; Deng,Yinqian; Zhang,Jing; Zhang,Jing; Wu,Zhixiong; Wu,Zhixiong; Wan,Xin; Wan,Xin; Liu,Qianfan; Liu,Qianfan; Huang,Hai; Huang,Hai; Hu,Pingsheng; Hu,Pingsheng; Zeng,Jiawei; Zeng,Jiawei; Zhou,Ding'an; Zhou,Ding'an

doi:10.3892/ijmm.2020.4652

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

Authors:
- Zexi Xu
- Yadong Li
- Dahong Wang
- Daoqiu Wu
- Jinyun Wang
- Lian Chen
- Yinqian Deng
- Jing Zhang
- Zhixiong Wu
- Xin Wan
- Qianfan Liu
- Hai Huang
- Pingsheng Hu
- Jiawei Zeng
- Ding'an Zhou
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Affiliations: Clinical Research Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China, Clinical College, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China, School of Clinical Laboratory Sciences, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China, School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou 550025, P.R. China, Department of Clinical Laboratory, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China
Published online on: June 19, 2020 https://doi.org/10.3892/ijmm.2020.4652
Pages: 1118-1134
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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