Mutated SASH1 promotes Mitf expression in a heterozygous mutated SASH1 knockin mouse model.
Int J Mol Med
; 46(3): 1118-1134, 2020 Sep.
Article
em En
| MEDLINE
| ID: mdl-32582980
ABSTRACT
The SAM and SH3 domaincontaining 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 microphthalmiaassociated transcription factor (Mitf) was uniformly induced in the tails of heterozygous BALB/c mice, and an increased quantity of Mitfpositive epithelial cells was also detected. An increased expression of Mitf and Mitfpositive cells was also demonstrated in the epithelial tissues of Y551DSASH1 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 SASH1mediated melanogenesis signaling pathway in vivo. SASH1 may function as a scaffold molecule for the assembly of a SASH1Mitf 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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Base de dados:
MEDLINE
Assunto principal:
Transtornos da Pigmentação
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Dermatopatias Genéticas
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Proteínas Supressoras de Tumor
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Fator de Transcrição Associado à Microftalmia
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article