Advances in the molecular genetics of deafness have vastly improved our ability to identify heritable hearing losses. Most familial moderate-to-profound congenital losses are inherited as an autosomal recessive trait. Heterogeneity is high, and to date 77 non-syndromic recessive loci have been identified and numbered sequentially DFNB1 through DFNB77 (DFN, deafness;B, recessive;integer, order of discovery). Twenty-eight causally-related genes have been cloned and encode proteins with a wide range of functions. Mutations in one gene, GJB2 at the DFNB1 locus, are responsible for half of moderate-to-profound autosomal recessive non-syndromic deafness (ARNSD) in many developed countries, making DFNB1 the most common type of hereditary congenital hearing loss. Mutations in SLC26A4 at the DFNB4 locus rank second and are associated with a Pendred Syndrome (PS)-DFNB4 phenotype. In aggregate, these advances have numerous important consequences. First, the identification of genes essential for normal auditory function has provided valuable insight into inner ear physiology at the molecular level and may one day lead to the development of novel therapies to treat deafness. Second, the use of genetic testing to diagnose ARNSD has changed the medical evaluation of the deaf person. Third, the identification of numerous genes that cause ARNSD, coupled with recent technological advances in microarray sequence capture and deep sequencing, is now making epidemiological studies of genetic deafness possible for the first time. This renewal application will focus on these three areas by completing specific aims: (1) To identify novel ARNSD genes;(2) To complete mutation screening of all genes implicated in non-syndromic deafness;(3) To study PS-DFNB4 as a complex disease. Completion of these specific aims will not only increase our understanding of the biology of hearing and deafness, but will be highly translational by improving the clinical diagnosis of non-syndromic deafness.
Autosomal recessive non-syndromic deafness (ARNSD) is extremely heterogeneous. To date 77 loci have been identified and 28 causally-related genes have been cloned. Studying these genes will increase our understanding of deafness, improve patient care, and ultimately lead to novel methods of treating ARNSD.
| Booth, Kevin T; Askew, James W; Talebizadeh, Zohreh et al. (2018) Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37. Genet Med : |
| Azaiez, Hela; Booth, Kevin T; Ephraim, Sean S et al. (2018) Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. Am J Hum Genet 103:484-497 |
| Imtiaz, Ayesha; Belyantseva, Inna A; Beirl, Alisha J et al. (2018) CDC14A phosphatase is essential for hearing and male fertility in mouse and human. Hum Mol Genet 27:780-798 |
| Booth, Kevin T; Azaiez, Hela; Kahrizi, Kimia et al. (2018) Exonic mutations and exon skipping: Lessons learned from DFNA5. Hum Mutat 39:433-440 |
| Booth, K T; Kahrizi, K; Babanejad, M et al. (2018) Variants in CIB2 cause DFNB48 and not USH1J. Clin Genet 93:812-821 |
| Booth, Kevin T; Kahrizi, Kimia; Najmabadi, Hossein et al. (2018) Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non-syndromic hearing impairment. J Med Genet 55:555-560 |
| Avenarius, Matthew R; Jung, Jae-Yun; Askew, Charles et al. (2018) Grxcr2 is required for stereocilia morphogenesis in the cochlea. PLoS One 13:e0201713 |
| Michel, Vincent; Booth, Kevin T; Patni, Pranav et al. (2017) CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival. EMBO Mol Med 9:1711-1731 |
| Shearer, A Eliot; Eppsteiner, Robert W; Frees, Kathy et al. (2017) Genetic variants in the peripheral auditory system significantly affect adult cochlear implant performance. Hear Res 348:138-142 |
| Lansdon, L A; Bernabe, H V; Nidey, N et al. (2017) The Use of Variant Maps to Explore Domain-Specific Mutations of FGFR1. J Dent Res 96:1339-1345 |
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