Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane

Legan, Kevin, Goodyear, Richard, Morin, Matias, Mencia, Angeles, Pollard, Hilary, Olavarrieta, Leticia, Korchagina, Julia Jurievna, Modiamo-Hoybjor, Silvia, Mayo, Fernando, Moreno, Felipe, Moreno-Pelayo, Miguel-Angel and Richardson, Guy (2013) Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane. Human Molecular Genetics, 23 (10). pp. 2551-2568. ISSN 0964-6906

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Abstract

Tecta is a modular, non-collagenous protein of the tectorial membrane, an extracellular matrix of the cochlea essential for normal hearing. Missense mutations in Tecta cause dominant forms of nonsyndromic deafness and a genotype-phenotype correlation has been reported in humans, with mutations in different Tecta domains causing mid- or high-frequency hearing impairments that are either stable or progressive. Three mutant mice were created as models for human Tecta mutations; the TectaL1820F, G1824D/+ mouse for zona pellucida (ZP) domain mutations causing stable mid-frequency hearing loss in a Belgian family, the TectaC1837G/+ mouse for a ZP-domain mutation underlying progressive mid-frequency hearing loss in a Spanish family, and the TectaC1619S/+ mouse for a zonadhesin-like (ZA) domain mutation responsible for progressive, high-frequency hearing loss in a French family. Mutations in the ZP and ZA domains generate distinctly different changes in the structure of the tectorial membrane. ABR thresholds in the 8-40 kHz range are elevated by 30-40 dB in the ZP-domain mutants, whilst those in the ZA-domain mutant are elevated by 20-30 dB. The phenotypes are stable and no evidence has been found for a progressive deterioration in tectorial membrane structure or auditory function. Despite elevated auditory thresholds, the Tecta mutant mice all exhibit an enhanced tendency to have audiogenic seizures in response to white noise stimuli at low sound pressure levels (≤84 dB SPL), revealing a previously unrecognised consequence of Tecta mutations. These results, together with those from previous studies, establish an allelic series for Tecta unequivocally demonstrating an association between genotype and phenotype.

Item Type: Article
Schools and Departments: School of Life Sciences > Neuroscience
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0447 Genes. Alleles. Genome
Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0460 Mutations
R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry
Depositing User: Kevin Legan
Date Deposited: 08 Jan 2014 15:02
Last Modified: 18 Nov 2014 14:29
URI: http://sro.sussex.ac.uk/id/eprint/47319

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