Affection Of SOX10 Mutation On Inner Ear Development With Bioinformatics Analysis

According to data released by WHO in 2017, about 5% of the world’s population(360 million) is disabled due to deafness, among which hereditary hearing loss is a common reason (http://www.who.int/mediacentre/factsheets/fs300/en/). It is reported that about 20% of children with congenital deafness can be found with inner ear deformities. The inner ear in human is composed of the auditory organ-cochlea and the balance organ-vestibule and three semicircular canals. Almost all the cells in inner ear were derived from the otic placode, except the melanocytes in stria vascularis and vestibulocochlear glial cells originated from the neural crest. In previous researches,SOX 10 (SRY-box 10) was known as an essential transcription factor regulating development of neural crest cells and was also widely expressed in otic placode or otic vesicle early. Mutations in SOX10 could induced several disorders related to neural crest defects, such as Waardenburg syndrome (WS), the most common syndromtic deafness, is characterized by pigmentation abnormalities and sensorineural hearing loss. In recent studies, it was suggested that WS patients with SOX10 mutations were more likely to incorporate with inner ear malformations.However, it is not clear yet that the regulation mechanisms of SOX10 in inner ear development.The classic Mondini malformation is the most common type of cochlear deformity, also known as type II incomplete separation (IP-Ⅱ), and is characterized by the fusion of the middle and apical turns of the cochlea resulting in a cystic apex with a normal basal turn leading to profound to severe sensorineural deafness. The pathogen of Mondini malformationis is still uncertain. Animal models commonly used in inner ear disease researches are mostly rodents, belong to the auditory system of late-maturing animals, can not provide accurate information in the inner ear development. While swine are extremely similar to human in inner ear morphology and development process, has gradually become a useful model for inner ear disorders.In the previously study, an albinotic miniature porcine model with SNHL was obtained carrying a heterozygous missense mutation in SOX10(C.325A>T, p.R109W),which corresponded to the 106th amino acid residue in human SOX10 protein, and was considered as a Waardenburg syndrome disease model.In present study, the morphological and hearing phenotypes of this SOX 10 mutation porcine model were further demonstrated. The high-throughput RNA-Seq was performed and through the bioinformatics analysis to explore the molecular mechanisms of SOX10 in inner ear development. Our study showed: (1) the 3D reconstruction of inner ear Micro-CT scan confirmed this procine model developed Mondini malformation (IP-II). Compared with the normal ones, the Mondini malformation caused by the SOX10 mutation began in the 28 days embryo, (2) there were 173 differentially expressed genes and 185 differentially expressed LncRNAs identified in 28-day-embryos inner ear tissue using RNA-Seq (including LncRNAs),(3) among 75 mondini malformation patients, 6 patients with Waardenburg syndrome were detected SOX10 mutations at multiple mutation sites, indicating that SOX10 mutations would result in syndromic Mondini malformations.It is convinced that with further studis on this SOX10 mutation porcine model we will have a better understanding on the role SOX10 playing on inner ear development.