Probing The Molecular Pathological Mechanism Underlying The Deafness In Albino Rongchang Swine

Microphthalmia transcription factor (Mitf), with a basic helix-loop-helixzipper (bHLH-Zip), is encoded by Mitf gene. Mitf regulates many celldifferentiation, such as melanocytes, retinal pigment epithelial cells (RPE) fromthe optic cup and many types of bone marrow-derived cells. According to thedifferent amino terminal, Mitf contains at least5subtypes. The subtypes of eachpromoter and the initial exon are different, and the expression in different tissues,whereas Mitf-M is specifically expressed in melanocytes and melanoma cells.Human Waardenburg syndrome is a kind of auditory-pigmentationdisorders characterized by autosomal dominant genetic disease, accounting for2%in congenital deafness. According to the clinical characteristics and geneticcriteria, this syndrome was divided into four subtypes. The Waardenburg type2Asyndrome and severe type Tietz syndrome is caused by mutations in MITF-Mgene, showed sensorineural deafness, heterochromia iridis and white forelock.Although a number of studies have shown that mutations in Mitf-M gene will leadto the lack of melanocytes derived from neural crest, resulting in hearing loss andother symptoms, but the pathological mechanism of Mitf gene on the auditorysystem remains unknown. Therefore, a careful study of the structure and functionof Mitf-m gene is very important for the gene diagnosis and molecularpathogenesis of deafness.We established the databases of normal porcine inner ear on anatomy,operation mode, morphology and auditory function and found porcine inner ear issimilar to human’s in struction and function. So it is very necessary to establish database in struction and function of normal porcine inner ear, which will be thebasement of next study. We constructed a albino Rongchang swine deafnesspedigrees, made genetic analysis and identify the causative gene-Mitf-M geneaccurately, which is specific for melanocytes. So this porcine pedigree has cleargenetic background and can be used in the otology field as big animal model.Weused homozygous mutant (Mitf-/-) and wild types (Mitf+/+) Rongchang swineat different developmental stages to make a comparative analysis ofmorphology and auditory function in inner ear and found that the deafness ofmutant types is caused by stria vascular pathological changes by the mutation ofMitf-M gene, which may be a reason for human Waardenburg syndrome type2Aand Tietz. The role of Mitf-M gene in the inner ear of stria vascularis and innerear melanocytes development were analyzed in the paper, and we explained thepathological mechanism of deafness caused by the mutation of Mitf-M, whichgives the key rules for early theropy,interven, and hair cells regeneration ofhuman related disease.The important findings of our study and its significance:1. It is the first time to report the ultrastructure of Rongchang porcine innerear;2. It is the first time to discover the deafness phenotype in albinoRongchang swine, which is consistent with human Waardenburg syndrome2Adeafness phenotype caused by Mitf-M gene mutation;3. It is the first time to report the relationship between Mitf-M genemutation and vascular stria pathological changes of albino Rongchang swine;4. Our study revealed the molecular pathogenesis of Waardenburgsyndrome2A.