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Originally published online as doi:10.2353/ajpath.2007.070068 on July 9, 2007

Published online before print July 9, 2007
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(American Journal of Pathology. 2007;171:608-616.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070068

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

Michel Guipponi*, Justin Tan{dagger}{ddagger}, Ping Z.F. Cannon*, Lauren Donley{dagger}, Pauline Crewther*, Maria Clarke{ddagger}, Qingyu Wu§, Robert K. Shepherd{dagger}{ddagger} and Hamish S. Scott*

From the Molecular Medicine Division,* The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia; The Bionic Ear Institute,{dagger} East Melbourne, Victoria, Australia; Department of Otolaryngology,{ddagger} University of Melbourne, East Melbourne, Victoria, Australia; and the Department of Cardiovascular Research,§ Berlex Biosciences, Richmond, California

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.




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