Modeling of pigmentation disorders associated with MITF mutation in Waardenburg syndrome revealed an impaired melanogenesis pathway in iPS‐derived melanocytes

Waardenburg Syndrome (WS) is a rare genetic disorder that leads to congenital hearing loss and pigmentation defects. Microphthalmia‐associated transcription factor (MITF) is one of its significant pathogenic genes. Despite the comprehensive investigation in animal models, the pathogenic mechanism is still poorly described in humans due to difficulties accessing embryonic tissues. In this work, we used induced pluripotent stem cells derived from a WS patient carrying a heterozygous mutation in the MITF gene c.626A>T (p.His209Leu), and differentiated toward melanocyte lineage, which is the most affected cell type involved in WS. Compared with the wild‐type cell line, the MITFmut cell line showed a reduced expression of the characteristic melanocyte‐related genes and a lesser proportion of mature, fully pigmented melanosomes. The transcriptome analysis also revealed widespread gene expression changes at the melanocyte stage in the MITFmut cell line. The differentially expressed genes were enriched in melanogenesis and cell proliferation‐related pathways. Interestingly, ion transport‐related genes also showed a significant difference in MITFmut‐induced melanocytes, indicating that the MITF mutant may lead to the dysfunction of potassium channels and transporters produced by intermediate cells in the cochlea, further causing the associated phenotype of deafness. Altogether, our study provides valuable insights into how MITF mutation affects WS patients, which might result in defective melanocyte development and the related phenotype based on the patient‐derived iPSC model. Warrensburg syndrome (WS) is a rare congenital disorder generally featuring congenital hearing loss and pigmentation abnormalities. Microphthalmia‐associated transcription factor (MITF) is one of its major pathogenic genes. In this study, we identified a pathogenic mutant in MITF from a Chinese pedigree of WS. A patient‐specific MITFmut‐induced pluripotent stem cell line was generated and differentiated into melanocytes to examine how the mutation affected melanocyte development. The cellular and transcriptomic characterization of the MITFmut cell line assisted in understanding the impact of reducing MITF protein expression on damaging the differentiation and functions of melanocytes, causing melanin defects in WS patients.