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

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

  • Pigment Cell Melanoma Res. 2023 Aug 9. doi: 10.1111/pcmr.13118.
Jie Wen 1 2,  Jian Song 3 4,  Jiale Chen 5,  Zhili Feng 1 2,  Qiancheng Jing 1 2,  Wei Gong 1 2,  Xiaoming Kang 1 2,  Lingyun Mei 3 4,  Chufeng He 3 4,  Lu Ma 2 6,  Yong Feng 1 2 4 7
Affiliations

Affiliations

  • 1 Department of Otorhinolaryngology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China.
  • 2 Institute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, China.
  • 3 Department of Otorhinolaryngology, Xiangya Hospital Central South University, Changsha, China.
  • 4 Province Key Laboratory of Otolaryngology Critical Diseases, Changsha, China.
  • 5 Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
  • 6 The Hengyang Key Laboratory of Cellular Stress Biology, Institute of Cytology and Genetics, Hengyang Medical School, University of South China, Hengyang, China.
  • 7 Hengyang Medical School, University of South China, Hengyang, China.
PMID: 37559350 DOI: 10.1111/pcmr.13118
Abstract

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.

Keywords

RNA-seq; Waardenburg syndrome; induced pluripotent stem cells; melanocytes; microphthalmia-associated transcription factor; neural crest cells.

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