Modelling of pigmentation disorders associated with MITF mutation in Waaredenburg Syndrome revealed an impaired melanogenesis pathway in iPS-derived melanocytes

ABSTRACT: Waardenburg Syndrome (WS) is a rare genetic disorder that leads to congenital hearing loss and pigmentation defects. MITF is one of its pathogenic genes. While studied extensively in animal models, its pathogenic mechanism still poorly described in humans due to the challenges in accessing embryonic tissues. In recent years, patient-derived human induced pluripotent stem cells(iPSCs) technology offers a promising approach for modeling human melanocyte development and hereditary disease. In this work, we make use of iPSCs derived from one WS patient carrying a heterozygous mutation in MITF gene. Accordingly, we establish a pipeline for profiling iPSCs during differentiation toward the melanocyte, which can be used to characterize the differentiation properties of the MITF+/- melanocytes. The MITF+/- cell lines showed a reduction in expression of the characteristic melanocyte-related gene expression profile. Analysis of the melanosome maturation process by electron microscopy revealed a lower percentage of mature, fully pigmented melanosomes. Compare with the WT cell lines, The transcriptome analysis reveals widespread gene expression changes at the stage of melanocyte in MITF+/- cell lines, and the differentially expressed genes(DEGs) were enriched with gene ontology (GO) of melanogenesis related pathway. Interesting, ion transport-related genes were also shown significantly difference in MITF+/- induced melanocyte, indicating the mutant MITF may lead to the dysfunction of potassium channels and transporters produced by intermediate cells in cochlear, further causes phenotypes of deafness. Altogether, our study provide valuable insights into how reduced MITF expression in WS patients might resulting in defective melanocyte development and related phenotype base on the patient-derived hiPSC model. The possibility of integrating laboratory data with clinical phenotypes will bring us toward precision medicine approaches in WS in the future.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200674 | GEO | 2022/11/13

REPOSITORIES: GEO