Regular Articles
Mice Deficient for the Type II Transmembrane Serine Protease, TMPRSS1/hepsin, Exhibit Profound Hearing Loss

https://doi.org/10.2353/ajpath.2007.070068Get rights and content

Defective proteolysis has been implicated in hearing loss through the discovery of mutations causing autosomal recessive nonsyndromic deafness in a type II transmembrane serine protease gene, TMPRSS3. To investigate their physiological function and the contribution of this family of proteases to the auditory function, we analyzed the hearing status of mice deficient for hepsin, also known as TMPRSS1. These mice exhibited profound hearing loss with elevated hearing thresholds compared with their heterozygous and wild-type littermates. Their cochleae showed abnormal tectorial membrane development, reduction in fiber compaction in the peripheral portion of the auditory nerve, and decreased expression of the myelin proteins myelin basic protein and myelin protein zero. In addition, reduced level of the large conductance voltage- and Ca2+-activated K+ channel was detected in the sensory hair cells of Tmprss1-null mice. We examined thyroid hormone levels in Tmprss1-deficient mice, as similar cochlear defects have been reported in animal models of hypothyroidism, and found significantly reduced free thyroxine levels. These data show that TMPRSS1 is required for normal auditory function. Hearing impairment present in Tmprss1-null mice is characterized by a combination of various structural, cellular, and molecular abnormalities that are likely to affect different cochlear processes.

Cited by (0)

Supported by Swiss National Science Foundation grant 3100A0-114077-1 (to M.G.), a Garnett Passe and Rodney Williams Memorial Foundation Research Training Fellowship (to M.G.), and a project grant (to M.G. and H.S.S.); by National Health and Medical Research Council (NHMRC) fellowships 171601 and 461204, NHMRC grants (project no. 215305 and program no. 257501), and the Nossal Leadership Award from the Walter and Eliza Hall Institute (to H.S.S.); and by the National Institute on Deafness and Other Communication Disorders (grant NO1-DC-3-1005), a Medical Research and Technology grant (Victoria, Australia), and the Marion and E.H. Flack Trust (to J.T.).

M.G. and J.T. contributed equally to this work.

Supplemental material for this article can be found on http://ajp.amjpathol.org.

Current address of M.G.: Division of Medical Genetics, University Hospital of Geneva, Geneva, Switzerland.

Current address of Q.W.: Molecular Cardiology/Nephrology & Hypertension Learner Research, Institute/ND50, The Cleveland Clinic Foundation, Cleveland, Ohio.

View Abstract