Identification of a novel c-KIT mutation inducing piebaldism and hearing loss in pigs by ENU mutagenesis

Abstract

As a rare autosomal dominant hypopigmentation disease, piebaldism is characterized by the presence of patchy albinism on the skin, and is mainly caused by the loss-of-function mutations in c-KIT gene. Congenital hearing loss is occasionally found as an expanded syndrome of piebaldism. However, the correlation between c-KIT mutations and piebaldism with hearing loss has not yet been described. Herein, we created a mutant strain of miniature pig through the N-ethyl-N-nitrosourea (ENU)-mediated mutagenesis, which showed severe piebaldism and congenital profound hearing loss. A genome-wide association study (GWAS) linked these phenotypes to the c.2430T>A transition mutation in exon 17 of c-KIT, resulting in an Asp810Glu substitution in the tyrosine kinase domain. The Asp810 was localized at the highly conserved DFG motif and the transition from Asp to Glu would deplete the kinase activity of c-KIT protein, finally inducing the degeneration of intermediate cells and hair cells in inner ear. The c-KIT c.2430T>A/+ pig is the first large animal model with a c-KIT loss-of-function mutation, showing piebaldism with hereditary hearing loss. It will serve as an experimental model for exploring the function of c-KIT during biological processes and the candidate therapies for c-KIT mutations related diseases.