Molecular Determinants of Usher Syndrome Disorder in Humans

点击翻译按钮获取中文摘要

Hearing loss (HL) is a highly variable phenotype that affects more than 70 million children worldwide. Among syndromic HL is Usher syndrome (USH), a neurosensory disorder defined by a bilateral sensorineural HL and a loss of vision due to retinitis pigmentosa (RP). Usher syndrome is classified into three clinical subtypes. A molecular diagnosis study suggested a frequency of 1/6000 individuals afflicted with USH in the US. Fourteen distinct genetic loci have been linked to the USH phenotype and genes for eleven of these loci have been identified. Genetic and functional studies of the gene/protein determinants of USH have been fruitful in elucidating the common molecular components of inner ear and retinal sensory epithelia. However, the molecular identities of many essential components of these two sensory organs are still unknown, precluding our understanding of molecular and cellular basis and precise mechanism of hearing and vision in general. Likewise, the known loci/gene mutations do not account for all known cases of USH. The long-­term goal of this research is to fully understand the mechanisms of inherited Usher syndrome and to develop therapeutic agents for the treatment and prevention of USH. The objective of the proposed research is to identify and characterize proteins essential to mammalian inner ear development, function and long-­term maintenance of retinal sensory cells. Our hypothesis is that if a mutated gene causes deafness and blindness, then the normal function of that gene will be necessary for hearing and vision. The rationale for the proposed research is that identifying a causative gene and understanding its normal function is essential for preventing hearing and vision loss and for the development of therapeutic agents to treat these impairments. The project addresses NIH’s mission to develop basic knowledge that may be translatable to reduce the burdens of human disability. In our preliminary data we have already identified two mutant genes: USH1K and USH1M, and have mapped the chromosomal positions (USH1H and USH1N) of two additional genes essential for auditory and visual function. The proposed experimental design comprises of two aims that include the ascertainment and clinically phenotype members of extended families segregating USH;; identification of new USH genes, characterization of their expression in the mouse inner ear and retina and determine the effect of identified variant of novel USH gene on the encoded protein in model systems. The project will advantageously combine human clinical assessment and genetic analyses with relevant to inner ear and retina development and function. It will be significant by advancing concerted methods and yielding basic new knowledge that is clinically relevant, with high potential to improve the molecular epidemiology, genetic diagnosis and counseling for USH.