Recent advances in the molecular genetics of deafness have vastly improved our ability to identify heritable hearing losses and have had several important consequences. First, the use of genetic testing to diagnose non-syndromic hearing loss (NSHL) has changed the medical evaluation of the deaf / hard-of-hearing person - after a history, physical examination and audiogram, genetic testing has become the next test ordered in the care of patients with presumed hereditary hearing impairment. Second, the identification of nearly one hundred genes that cause NSHL, coupled with technological advances in sequence capture and deep sequencing, has made robust epidemiological studies of genetic deafness possible for the first time. Third, understanding the genetic basis for normal auditory function is providing insight into inner ear physiology at the molecular level that will lad one day to the development of novel gene-specific and even mutation-specific therapies to treat hearing loss. Over the past granting period, we have focused on the following three specific aims: (1) To identify novel genetic causes of autosomal recessive non-syndromic hearing loss (ARNSHL);(2) To complete mutation screening of the coding sequence of all genes implicated in NSHL;(3) To study the Pendred syndrome / DFNB4 disease spectrum. In this competitive renewal, we will build on these accomplishments by completing the following specific aims:
Specific Aim 1. To identify genetic mutations in regulatory elements that contribute to NSHL Hypothesis. Mutations in regulatory elements contribute to NSHL. These mutations can be identified by: a) studying a carefully selected patient population that is enriched for non-coding disease-causing variants and for whom full phenotypic and clinical data are available;and, b) applying targeted sequence capture and massively parallel sequencing to regulatory regions coupled with integrated analysis of murine ChIP-Seq data, ENCODE data and in silico data.
Specific Aim 2. To compare simple and complex haplotypes in two well-defined populations - one with age-related hearing loss and one with normal hearing. Hypothesis. Custom modifications of the Galaxy pipeline make it possible to reconstruct unphased haplotypes for all NSHL genes included on OtoSCOPE(R). By studying two well-defined populations, one with and the other without age-related hearing loss, we will be able to identify at-risk and protective haplotypes and haplotype combinations that are associated with age-related hearing loss. The successful completion of these aims will have a major impact on our understanding of genetic deafness and offer novel insights into how specific protein-protein interactions contribute to age-related hearing loss.
This competitive renewal is focused on two questions germane to non-syndromic hearing loss: 1) the identification of non-coding deafness-causing mutations in regulatory elements, with a particular focus on promoters;and, 2) the evaluation of simple and complex haplotypes as contributing factors to age-related hearing loss (ARHL). The successful completion of these aims will have a major impact on our understanding of the genetics of hearing loss and offer novel insights into how specific protein-protein interactions contribute to ARHL.
|Nessler, Ian J; Litman, Jacob M; Schnieders, Michael J (2016) Toward polarizable AMOEBA thermodynamics at fixed charge efficiency using a dual force field approach: application to organic crystals. Phys Chem Chem Phys 18:30313-30322|
|Sloan-Heggen, Christina M; Bierer, Amanda O; Shearer, A Eliot et al. (2016) Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet 135:441-50|
|Moteki, Hideaki; Yoshimura, Hidekane; Azaiez, Hela et al. (2015) USH2 caused by GPR98 mutation diagnosed by massively parallel sequencing in advance of the occurrence of visual symptoms. Ann Otol Rhinol Laryngol 124 Suppl 1:123S-8S|
|Jayawardena, Asitha D L; Shearer, A Eliot; Smith, Richard J H (2015) Sensorineural Hearing Loss: A Changing Paradigm for Its Evaluation. Otolaryngol Head Neck Surg 153:843-50|
|Mori, Kentaro; Moteki, Hideaki; Kobayashi, Yumiko et al. (2015) Mutations in LOXHD1 gene cause various types and severities of hearing loss. Ann Otol Rhinol Laryngol 124 Suppl 1:135S-41S|
|Moteki, Hideaki; Azaiez, Hela; Booth, Kevin T et al. (2015) Hearing loss caused by a P2RX2 mutation identified in a MELAS family with a coexisting mitochondrial 3243AG mutation. Ann Otol Rhinol Laryngol 124 Suppl 1:177S-83S|
|Shearer, A Eliot; Smith, Richard J H (2015) Massively Parallel Sequencing for Genetic Diagnosis of Hearing Loss: The New Standard of Care. Otolaryngol Head Neck Surg 153:175-82|
|Sloan-Heggen, Christina M; Babanejad, Mojgan; Beheshtian, Maryam et al. (2015) Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran. J Med Genet 52:823-9|
|Moteki, H; Azaiez, H; Booth, K T et al. (2015) Comprehensive genetic testing with ethnic-specific filtering by allele frequency in a Japanese hearing-loss population. Clin Genet :|
|LuCore, Stephen D; Litman, Jacob M; Powers, Kyle T et al. (2015) Dead-End Elimination with a Polarizable Force Field Repacks PCNA Structures. Biophys J 109:816-26|
Showing the most recent 10 out of 118 publications