Abstract
Mutations in the type II transmembrane serine protease 3 (TMPRSS3) gene cause non-syndromic autosomal recessive deafness (DFNB8/10), characterized by congenital or childhood onset bilateral profound hearing loss. In order to explore the physiopathology of TMPRSS3 related deafness, we have generated an ethyl-nitrosourea-induced mutant mouse carrying a protein-truncating nonsense mutation in Tmprss3 (Y260X) and characterized the functional and histological consequences of Tmprss3 deficiency. Auditory brainstem response revealed that wild type and heterozygous mice have normal hearing thresholds up to 5 months of age, whereas Tmprss3(Y260X) homozygous mutant mice exhibit severe deafness. Histological examination showed degeneration of the organ of Corti in adult mutant mice. Cochlear hair cell degeneration starts at the onset of hearing, postnatal day 12, in the basal turn and progresses very rapidly toward the apex, reaching completion within 2 days. Given that auditory and vestibular deficits often co-exist, we evaluated the balancing abilities of Tmprss3(Y260X) mice by using rotating rod and vestibular behavioral tests. Tmprss3(Y260X) mice effectively displayed mild vestibular syndrome that correlated histologically with a slow degeneration of saccular hair cells. In situ hybridization in the developing inner ear showed that Tmprss3 mRNA is localized in sensory hair cells in the cochlea and the vestibule. Our results show that Tmprss3 acts as a permissive factor for cochlear hair cells survival and activation at the onset of hearing and is required for saccular hair cell survival. This mouse model will certainly help to decipher the molecular mechanisms underlying DFNB8/10 deafness and cochlear function.
Highlights
Mutations in the type II transmembrane serine protease 3 (TMPRSS3) gene cause non-syndromic autosomal recessive deafness (DFNB8/10), characterized by congenital or childhood onset bilateral profound hearing loss
TMPRSS3 is a type II transmembrane serine protease, structurally defined by a transmembrane domain located near the N terminus; a low density lipoprotein receptor A domain, which binds calcium [4] and low density lipoprotein [5]; a scavenger receptor cysteine-rich domain that is involved in protein-protein interaction [6]; and a C-terminal serine protease domain from the S1 family of the SA clan of serine-type peptidases for which the prototype is chymotrypsin [7]
The number of missing hair cells was counted in six segments of 1 mm each normally containing a mean number of 110 inner hair cells (IHCs) and 125 ϫ 3 outer hair cells (OHCs) per mm
Summary
The care and use of animals followed the animal welfare guidelines of INSERM, under the approval of the French “Ministere de l’Alimentation, de l’Agriculture et de la Peche”. All efforts were made to minimize the number of animals used and their suffering. Ingenium Pharmaceuticals AG has developed a large library of cryopreserved mutant mouse sperm derived from a chemical mutagenesis program, in which male C3HeB/FeJ mice were mutagenized with ethyl-nitrosourea. The screen for deleterious mutations in the Tmprss gene was performed in G1 animals that were derived from the mating of mutagenenized G0 males with untreated C3HeB/FeJ females. A mutation search was performed using heteroduplex formation analysis by temperature gradient capillary electrophoresis
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