Researchers from National Institute on Deafness and Other Communication Disorders (NIDCD) developed a small-molecule drug therapy that can preserve hearing in a mouse.
Congenital hearing loss can be hereditary or due to other factors present either in-utero (prenatal) or at the time of birth. Such hearing impairment is due to the mutation of a region of chromosome four called DFNA27. Researchers from NIDCD and University of Iowa revealed the molecular mechanism of DFNA27 that can aid in a new treatment strategy for deafness. The research led by Thomas B. Friedman, Ph.D., chief of the Laboratory of Human Molecular Genetics (NIDCD) and Robert J. Morell, Ph.D. effectively restored hearing in mice at lower frequencies. Prior studies by the team identified the LMG2 family of genes that was responsible for hereditary deafness. Now they located the deafness-causing mutation to a region on chromosome four called DFNA27.
The RE1 Silencing Transcription Factor (REST) gene of the mouse is regulated through an unusual mechanism in the sensory cells of the inner ear. This regulation is crucial to explain the form of DFNA27 progressive deafness in mice, hence the team reexamined the location of mouse REST gene in the four chromosomal region of DFNA27. When the coding sequences of a protein in the exons, which are a part of Precursor mRNAs in REST genes was deleted the mice became deaf. The main function of REST genes is to shut off genes that need to be active only in a very few cell types. This proved that the mutation in the exon 4 of DFNA27 interferes with the inactivation of REST in sensory hair cells. The exon 4 in the REST mRNA acts like a switch in sensory hair cells, which when turned on is important for hair cell survival and hearing. REST genes can restrict genetic expression through histone deacetylation. The researchers used the exon 4-deficient mice as a model for DFNA27 deafness and blocked the process using small-molecule drugs to partially restore hearing. The study was published in the online journal Cell on June 27, 2018.