Modeling of pigmentation disorders associated with MITF mutation in Waardenburg syndrome revealed an impaired melanogenesis pathway in iPS-derived melanocytes.
Pigment Cell Melanoma Res
; 37(1): 21-35, 2024 Jan.
Article
en En
| MEDLINE
| ID: mdl-37559350
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Trastornos de la Pigmentación
/
Síndrome de Waardenburg
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Pigment Cell Melanoma Res
Asunto de la revista:
NEOPLASIAS
Año:
2024
Tipo del documento:
Article
País de afiliación:
China