ENLARGED VESTIBULAR AQUEDUCTS (EVA) We analyzed our cohort of over 100 EVA patients that have been evaluated at the NIH Clinical Center to determine the results of SLC26A4 mutation testing in patients with unilateral (one-sided) EVA. Genetic causes are often not considered to be likely in patients with unilateral hearing loss, so the importance of this study was to determine if SLC26A4 mutation testing was useful for the diagnosis of unilateral EVA. We identified patients with all possible SLC26A4 genotype results: one, two, or no detectable mutant alleles of SLC26A4. This data confirms the study hypothesis that SLC26A4 testing is useful in patients with unilateral EVA. The different genotype results (i.e. 0 vs. 1 vs. 2 mutant alleles) are all associated with different thyroid phenotypes, hearing loss outcomes, and probability of EVA affecting siblings of the patient. Therefore SLC26A4 mutation test results can provide important rehabilitative and prognostic counseling for patients and families. The resulting manuscript is in press in JAMA Otolaryngology-Head and Neck Surgery (ref. 1). We ascertain families with multiple members with nonsyndromic EVA that is not associated with detectable SLC26A4 mutations or Pendred syndrome. Our hypothesis is that these families segregate recessive alleles at one or more other genetic loci that cause nonsyndromic EVA. We are using those families in a linkage-based exome sequencing strategy to identify other genetic causes of EVA. We have used recombination breakpoint mapping to define a region of shared linkage overlap containing the SLC26A4 gene on chromosome 7 to search for occult (unidentified) mutations of SLC26A4 in families segregating nonsyndromic EVA with only one detectable mutant allele of SLC26A4. Our hypothesis is that these families segregate a second, unidentified, mutation of SLC26A4. We are using massively parallel sequencing to sequence the entire region of shared overlap to identify occult mutations. We previously generated a doxycycline-inducible Slc26a4-expression mouse line. This transgenic mouse line allows us to manipulate Slc26a4 expression (on an Slc26a4-knockout background) by the administration of doxycycline in drinking water. We have manipulated doxycycline administration to generate mice in which there is significant residual hearing and isolated EVA at the age of one month. Longitudinal analysis of these mice has revealed large fluctuations of hearing from 1-3 months of age, followed by progressive hearing loss from 9-12 months of age. The hearing loss is associated with reduction of the endocochlear potential, pathology of the intermediate layer of the stria vascularis, which generates the endocochlear potential, and evidence of oxidative stress and damage. The pattern of hearing loss remarkably resembles that observed in many human patients with EVA and validates the potential of this animal model to further explore the pathophysiology and potential therapeutic interventions to prevent hearing loss fluctuation and progression. We participated in a collaboration with Dr. Philine Wangemann of Kansas State University to develop a transgenic mouse system and experiment to determine if Slc26a4 expression in the developing mouse ear was required in the endolymphatic sac, cochlear, or both for the acquisition of normal hearing. The results demonstrated that expression in the endolymphatic sac was sufficient to acquire and maintain normal hearing. The results were reported in PLoS Genetics (ref. 2). This supports a model in which loss of Slc26a4 function in the sac leads to acidification and enlargement of the endolymph compartment of the inner ear, which secondarily affects the stria vascularis to reduce the endocochlear potential to cause hearing loss. The results also suggest replacement of Slc26a4 in the endolymphatic sac as a potential intervention to prevent hearing loss. TMC GENES We previously generated and reported mice with knockout (null) alleles of Tmc1 and Tmc2. We had shown that Tmc1 and Tmc2 are functionally redundant and required for mechanotransduction in the stereocilia of postnatal cochlear and vestibular sensory hair cells. The results suggested that TMC1 and TMC2 may comprise the hair cell mechanoelectrical transduction channel, or are intimately involved in its development and/or function. We are continuing to test this hypothesis by localization of TMC1 and TMC2 proteins in hair cells. We also collaborated with Dr. Jeffrey Holt to characterize the whole-cell and single-channel mechanoelectrical transduction currents in mice segregating mutant alleles of Tmc1 and Tmc2. The results show distinctly different hair cell single-channel transduction current properties (ion permeability and conductance) associated with the expression or presence of TMC1 in comparison to TMC2 in comparison to a mutated form of TMC1. The data are consistent with the hypothesis that TMC1 and TMC2 are components of the mechanotransduction channel. This study was published in Neuron (ref. 3). We generated knockout mice for Tmc6 and Tmc8 to better understand the function(s) of Tmc genes and proteins. Mutations in human TMC6 or TMC8 genes cause epidermodysplasia verruciformis, a recessive disease resulting in chronic cutaneous HPV infections (papillomas or warts) with increased susceptibility to non-melanoma skin cancers. We have done extensive RNA expression analyses to show that Tmc6 and Tmc8 are primarily expressed in lymphoid cells and tissues and lung and skin, and primarily during development. The homozygous knockout mice have no obvious phenotypic abnormalities, so we are collaborating with Dr. Paul Lambert to determine if these mice have alterations in their susceptibility or response to papillomavirus infection. DFNA34 HEARING LOSS We mapped a novel nonsyndromic hearing loss locus, DFNA34, in a single large family. We used recombinations to define a critical map interval in which the gene and mutation must be located. We identified a likely mutation in a gene in which other mutations cause hearing loss associated with autoinflammatory disease. In order to confirm this mutation as causative, we used massively parallel sequencing as well as conventional Sanger dideoxy sequencing to rule out mutations in any of the other genes in the critical map interval. We are currently attempting to detect expression of the candidate gene in the inner ear to determine whether the hearing loss is caused by an intrinsic defect of cochlear function or whether the hearing loss is secondary to systemic autoinflammation. We are also collaborating with Drs. Daniel Kastner and Raphaela Goldbach-Mansky to study the patients for evidence of cochlear inflammation on magnetic resonance imaging studies at the NIH Clinical Center;this is a finding which is observed in patients with autoinflammatory hearing loss. We also plan a collaborative study of the patient leukocytes to detect abnormalities consistent with autoinflammation. COLLABORATIVE PROJECTS We collaborated with Dr. Kenneth Kraemer (NCI) to characterize the auditory phenotype of patients with xeroderma pigmentosum, a genetically heterogeneous disease characterized by defective DNA repair and susceptibility to skin cancer. The results indicated that hearing loss was correlated with neurodegeneration in the subset of XP patients who have neurodegeneration. This study was published in Brain (ref. 4). We also collaborated with Dr. Kraemer to characterize the phenotype of a patient with melanoma, DNA repair deficiency and deafness associated with a chromosomal translocation. This translocation revealed chimeric negative regulation of the p14ARF and TBX1 genes, accounting for the phenotype of the patient. The results were published in Human Mutation (ref. 5)

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Muskett, Julie A; Chattaraj, Parna; Heneghan, John F et al. (2016) Atypical patterns of segregation of familial enlargement of the vestibular aqueduct. Laryngoscope 126:E240-7
Nishio, Ayako; Ito, Taku; Cheng, Hui et al. (2016) Slc26a4 expression prevents fluctuation of hearing in a mouse model of large vestibular aqueduct syndrome. Neuroscience 329:74-82
Brewer, Carmen C; Zalewski, Christopher K; King, Kelly A et al. (2016) Heritability of non-speech auditory processing skills. Eur J Hum Genet 24:1137-44
Rehman, A U; Friedman, T B; Griffith, A J (2016) Unresolved questions regarding human hereditary deafness. Oral Dis :
Ito, T; Nishio, A; Wangemann, P et al. (2015) Progressive irreversible hearing loss is caused by stria vascularis degeneration in an Slc26a4-insufficient mouse model of large vestibular aqueduct syndrome. Neuroscience 310:188-97
Zalewski, Chris K; Chien, Wade W; King, Kelly A et al. (2015) Vestibular Dysfunction in Patients with Enlarged Vestibular Aqueduct. Otolaryngol Head Neck Surg 153:257-62
Morozko, Eva L; Nishio, Ayako; Ingham, Neil J et al. (2015) ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells. Hum Mol Genet 24:609-24
Kurima, Kiyoto; Ebrahim, Seham; Pan, Bifeng et al. (2015) TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia. Cell Rep 12:1606-17
Ito, Taku; Li, Xiangming; Kurima, Kiyoto et al. (2014) Slc26a4-insufficiency causes fluctuating hearing loss and stria vascularis dysfunction. Neurobiol Dis 66:53-65
King, Kelly A; Gordon-Salant, Sandra; Pawlowski, Karen S et al. (2014) Hearing loss is an early consequence of Npc1 gene deletion in the mouse model of Niemann-Pick disease, type C. J Assoc Res Otolaryngol 15:529-41

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