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Pilot study of large-scale production of SOX10 mutant causes inner ear malformation in pigs by ENU mutagenesis
18 April 2018 (online)
Mondini malformation is common inner ear deformities, which causes profound hearing loss in young children, but the critical pathology of inner ear and the molecular factors still be unknown because of lacking the ideal animal model. N-ethyl-N-nitrosourea (ENU) mutagenesis is a powerful tool to generate mutants on a large scale efficiently, and to discover genes with novel functions at the whole-genome level in Caenorhabditis elegans, flies, zebrafish and mice, but it has never been tried in large model animals. We describe a successful systematic three-generation ENU mutagenesis screening in pigs and the establishment of the Chinese Swine Mutagenesis Consortium. A total of 6770 G1 and 6800 G3 pigs were screened, 36 dominant and 91 recessive novel pig families with various phenotypes were established. As examples, the mutation of SOX10 (R109W) in pig causes inner ear malfunctions and mimics human Mondini dysplasia, whereas upregulated expression of FBXO32 is associated with congenital splay legs. Our results indicated that these SOX10 mutation miniature pigs were characterized by the incomplete partition of cochlea, a cystic apex caused by fusion from middle and apical turns, cochlear modiolar defects and shortened cochlear duct. The most significantly enriched pathways associated with the down-regulated DEGs were inflammatory mediator regulation of TRP channels, arachidonic acid metabolism, and salivary secretion, while the up-regulated DEGs were systemic lupus erythematosus and alcoholism. In conclusion, the inner ear malformation in SOX10 p.R109W mutation miniature porcine model that provides useful target genes and pathways for the future investigation into the molecular mechanisms of SOX10 on inner ear development.