title: Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane.
abstract: Tecta is a modular, non-collagenous protein of the tectorial membrane (TM), an extracellular matrix of the cochlea essential for normal hearing. Missense mutations in Tecta cause dominant forms of non-syndromic 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 Tecta(L1820F,G1824D/+) mouse for zona pellucida (ZP) domain mutations causing stable mid-frequency hearing loss in a Belgian family, the Tecta(C1837G/+) mouse for a ZP-domain mutation underlying progressive mid-frequency hearing loss in a Spanish family and the Tecta(C1619S/+) 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 TM. Auditory brainstem response 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 TM 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.
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
authors.forename: P Kevin
authors.initials: PK
authors.lastname: Legan
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Goodyear
authors.forename: Matías
authors.initials: M
authors.lastname: Morín
authors.forename: Angeles
authors.initials: A
authors.lastname: Mencia
authors.forename: Hilary
authors.initials: H
authors.lastname: Pollard
authors.forename: Leticia
authors.initials: L
authors.lastname: Olavarrieta
authors.forename: Julia
authors.initials: J
authors.lastname: Korchagina
authors.forename: Silvia
authors.initials: S
authors.lastname: Modamio-Hoybjor
authors.forename: Fernando
authors.initials: F
authors.lastname: Mayo
authors.forename: Felipe
authors.initials: F
authors.lastname: Moreno
authors.forename: Miguel-Angel
authors.initials: MA
authors.lastname: Moreno-Pelayo
authors.forename: Guy P
authors.initials: GP
authors.lastname: Richardson
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D003638:Deafness / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D020195:Epilepsy, Reflex / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006199:Hair Cells, Auditory, Inner / Q000473:pathology; D006720:Homozygote; D006801:Humans; D008297:Male; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D020409:Molecular Motor Proteins / Q000378:metabolism; D020125:Mutation, Missense; D009925:Organ of Corti / Q000473:pathology; D010641:Phenotype; D013680:Tectorial Membrane / Q000378:metabolism / Q000473:pathology*
chemical_list: D016326:Extracellular Matrix Proteins; D058851:GPI-Linked Proteins; D020409:Molecular Motor Proteins; C498720:Pres protein, mouse; C491350:TECTA protein, human