Treacher Collins Syndrome Gene Screening And Bor And Eya4 Gene Function In The Inner Ear Development Research

Partl A novel mutation in the TCOF1gene found in two Chinese cases of Treacher Collins syndromeObjective:To analyze the clinical features, hearing rehabilitation and family-related gene mutations in the Chinese cases of Treacher Collins syndrome (TCS). The purposeof this study is toemphasize the genetic research result correlating with the clinical assessment of TCS in Chinese familiesMethods:Six patients with tentative diagnosis and family membersof two patientswere analyzed in this study. The analysis included medical histories, clinical analysis, hearing tests and genetic tests. The TCOF1, POLR1C and POLR1D genes were sequenced to identify the pathogenic mutation responsible for the development of TCS.Results:The two TCS cases exhibited high phenotypic variability. One novel heterozygous mutation (c.4420C>T) in the TCOF1gene was identified; these mutations were found in the TCS patients but not in any of their unaffected family members or the200unrelated control subjects.Conclusions:A novel TCOF1c.4420C>T mutation can be a cause of TCS in Chinese. We think that genetic studiestoassess patients with mandibulofacial dysostosis mayassistinmaking TCS diagnosis and providing consultant for their families. Part2BOR and Eya4deficiency impairs hearing and balance ability in zebrafishObjective:Deafness effects the health of human seriously. Hearing loss affects approximately27million in the china alone and has a high incidence-about278million people suffer from moderate to severe hearing loss in the world. It can be safely assumed that all children with congenital sensory hearing loss would have detectable abnormalities in their inner ears if they could be examined histologically. Development of therapies to treat hearing loss and balance disorders is complicated by the diversity of disease processes leading to functional loss and the current approaches available for treatment. Despite the significant impact of hearing and balance disorders on the general population there are currently no dedicated pharmaceuticals that target the inner ear. Incidence reduction, early detection, and early treatment of hearing losshave become a common interest of society. Prevention and treatment of Inner Ear Malformations and sensorineural deafness basic research is still hot and difficult.Methods:Human deletions in EYA4cause a dominant form of sensorineural hearing loss, which sometimes is accompanied by late-onset dilated cardiomyopathy. Eya4molecules are evolutionarily conserved transcriptional coactivatorsthat participate in the development of multiple organs, including the eye, pituitary gland, muscle, kidney, inner ear and heart. Eya proteins contain a highly conserved carboxyl domain with phosphatase activity and interaction sites for Sineoculis (Six) proteins, and a variable amino domain with unknown functions Interactions with Six proteins permit Eya proteins to translocate into the nucleus where phosphatase activity releases transcriptional repression caused by Six-Dachshund and other molecules. The gene targets regulated by Eya4, Six and Dachshund in the ear or heart are unknown.Results:Eya4transcript of the gene was present in unfertilized eggs, suggesting a maternal origin. Eya4expression is rather dynamic. The onset of eya4in the otic organs was detected weakly in the otic placode at14hpf. By14hours post-fertilization (hpf), eya4transcripts were detected at two distinct sites in the otic placode region. This patternpersisted through further otic placode development assessed at19.5hpf. At19.5hpf, an additional cluster of cells, anterior to the otic placode, which may give rise to ganglion neuroblasts, also expressed eya4. By24hpf, eya4expression was most prominent along the anterior and posterior axis of the ventral side of the otic vesicle from where the progenitors of sensory epithelial cells originate.At36hpf this expression pattern was maintained, albeit with some broadening of ventral eya4expression. By5dpf, eya4expression was expressed hair cellsConclusions:In summary, eya4in vivo may regulate six4.1, promoting loss of hair cell morphogenesis. This is the first study exploring regulated Six and Dachshund in inner ear malformation and deafness.