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

Area of Science:

• Genetics and Molecular Biology
• Dermatology
• Cell Biology

Background:

• SAM and SH3 domain-containing 1 (SASH1) gene variants are linked to dyschromatosis universalis hereditaria (DUH) and other pigmentary genodermatoses.
• Previous research on mutated SASH1 has been primarily limited to in vitro studies.
• Understanding the in vivo molecular pathology of SASH1 mutations is crucial for DUH pathogenesis.

Purpose of the Study:

• To establish a mouse model recapitulating DUH phenotypes caused by SASH1 mutations.
• To investigate the in vivo molecular mechanisms underlying SASH1-mediated pigment abnormalities.
• To identify the role of microphthalmia-associated transcription factor (Mitf) in SASH1-related melanogenesis.

Main Methods:

• Generation of a heterozygous BALB/c mouse model with a knocked-in human SASH1 c.1654 T>G (p. Tyr 551Asp, Y551D) mutation.
• In vivo functional experiments to assess SASH1 Y551D effects on gene expression and cell populations in mouse tails.
• Analysis of Mitf expression in epithelial tissues of affected individuals and in vitro cell cultures.

Main Results:

• The SASH1 Y551D mutation uniformly increased microphthalmia-associated transcription factor (Mitf) expression in mouse tails.
• An increased quantity of Mitf-positive epithelial cells was observed in the mouse model and in affected individuals.
• In vitro studies confirmed that Y551D SASH1 upregulates Mitf expression, indicating its role in melanogenesis.

Conclusions:

• Upregulation of Mitf is a key effector in the Y551D SASH1-mediated melanogenesis pathway in vivo.
• SASH1 may act as a scaffold molecule, forming a complex with Mitf to regulate its nuclear expression.
• This mechanism contributes to hyperpigmentation in DUH and other pigment abnormality-related genodermatoses.