Mutated SASH1 promotes Mitf expression in a heterozygous mutated SASH1 knock-in mouse model
Mutated SASH1 promotes Mitf expression in a heterozygous mutated SASH1 knock-in mouse model
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DOI：
10.3892/ijmm.2020.4652
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发表时间：
2020-09-01
影响因子：
5.4
通讯作者：
Zhou, Ding'an
中科院分区：
文献类型：
--
作者：
Xu, Zexi;Li, Yadong;Zhou, Ding'an
SAM和SH3结构域1(SASH1)基因是遗传性泛色素性色素异常症(DUH)的致病基因，这些基因导致DUH的病理表型，SASH1变异体在各种遗传性皮肤病中调节人类皮肤的异常色素沉着表型。然而，对突变的SASH1基因的研究仅限于体外研究。本研究首次建立了人SASH1c.1654 T>；G(p.Tyr 551Asp，Y551D)突变的杂合子BALB/c小鼠模型，总结了SASH1突变所致DUH的分子病理表型。Y551DSASH1的活体功能实验表明，在杂合子BALB/c小鼠的尾巴中，均能诱导小眼球相关转录因子(MITF)的表达增加，并检测到MITF阳性的上皮细胞数量增加。在Y551D-SASH1感染者的上皮组织中，MITF和MITF阳性细胞的表达也增加。在本研究中还发现Y551DSASH1在体外也能增加MITF的表达。综上所述，这些发现表明MITF的上调是Y551D SASH1介导的体内黑素生成信号通路的真正效应者。SASH1可能作为一个支架分子组装SASH1-MITF分子复合体，调节细胞核中MITF的表达，从而促进DUH和其他与色素异常相关的遗传性皮肤病的色素沉着表型。
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, andSASH1variants have been shown to regulate the abnormal pigmentation phenotype in human skin in various genodermatoses. However, investigations into the mutatedSASH1gene have been limited toin vitrostudies. In the present study, to recapitulate the molecular pathological phenotypes of individuals with DUH induced bySASH1mutations, a heterozygous BALB/c mouse model, in which the humanSASH1c.1654 T>G (p. Tyr 551Asp, Y551D) mutation was knocked in was first generated. Thein vivofunctional experiments on Y551DSASH1indicated 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-SASH1affected individuals. In the present study, Mitf expression was also found to be increased by Y551DSASH1 in vitro. Taken together, these findings indicate that the upregulation of Mitf is the bona fide effector of the Y551D SASH1-mediated melanogenesis signaling pathwayin 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.