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 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 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.

Increased Spontaneous Otoacoustic Emissions in Mice with a Detached Tectorial Membrane

“…Although some Otoa KO mice at 6-7 months of age retained SOAEs at low frequencies, none of the older mice exhibited high-frequency SOAEs, as their responses to high f2 frequencies were The total number of mice with SOAEs and the total number of SOAEs observed in each mouse group is provided in the legend. The position of Hensen's stripe in WT mice is also indicated in panel A along the abscissa to show that it is present in controls but only for more basal locations encoding frequencies greater than~15 kHz (Cheatham et al 2014;Legan et al 2014). Panel C provides a plot of SOAE magnitude versus SOAE frequency for WT (black squares), Ceacam16 KOs (blue triangles), and Otoa KOs (red open circles).…”

“…The body of the TM contains collagen fibrils embedded in an unusual striated-sheet matrix, the major components of which are alpha and betatectorin (Tecta and Tectb, respectively) and Ceacam16 (Legan et al 1997;Zheng et al 2011;Kammerer et al 2012;Cheatham et al 2014). In the absence of functional Tecta, the TM becomes completely de-tached from the organ of Corti and the animals suffer a significant hearing loss (Legan et al 2000;MorenoPelayo et al 2008;Legan et al 2014).…”

“…The increased number of SOAEs encountered in Ceacam16 KO mice correlates with the absence of Hensen's stripe, a ridge that projects down from the undersurface of the TM. This structure is closely apposed to and lies just medial to the hair bundles of IHCs but is only observed in the basal 60 % of the mouse cochlea, i.e., for regions coding frequencies above 15 kHz (Müller et al 2005;Cheatham et al 2014;Legan et al 2014). Although striated-sheet matrix fails to form in Ceacam16 KO mice and despite the appearance of large holes appearing in the main body of the TM, especially in the apical, low-frequency end of the cochlea, the spatial distribution of these structural defects does not correlate with the observed SOAE frequencies.…”

Novel <b><i>TECTA </i></b>Mutations Identified in Stable Sensorineural Hearing Loss and Their Clinical Implications

“…Studies have attempted to explain the genotype-phenotype correlation for TECTA mutations using mutant mouse models [Legan et al, 2005[Legan et al, , 2014Xia et al, 2010]. They developed transgenic mouse lines that carried the p.C1509G, p.C1619S, p.L1820F, p.G1824D, p.C1837G, and p.Y1870C variants of Tecta.…”

“…Missense mutations in the vWFD4 subdomain seemed to be crucial for the development of the marginal band, covernet, and Hensen's stripe tectorial membrane features. Missense mutations in the ZP domain seemed to be important for locating these peripheral features correctly [Legan et al, 2014]. Therefore, it can be recognized that the vWFD4 subdomain mutations and ZP domain mutations caused distinctive structural deficits and we can assume that the genotype-phenotype correlations would be different.…”