title: Mice deficient for the type II transmembrane serine protease, TMPRSS1/hepsin, exhibit profound hearing loss.
abstract: 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 Ca(2+)-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.
authors.affiliation: Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.forename: Justin
authors.initials: J
authors.lastname: Tan
authors.forename: Ping Z F
authors.initials: PZ
authors.lastname: Cannon
authors.forename: Lauren
authors.initials: L
authors.lastname: Donley
authors.forename: Pauline
authors.initials: P
authors.lastname: Crewther
authors.forename: Maria
authors.initials: M
authors.lastname: Clarke
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Wu
authors.forename: Robert K
authors.initials: RK
authors.lastname: Shepherd
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
mesh_terms: D000818:Animals; D001309:Auditory Threshold; D015153:Blotting, Western; D003051:Cochlea / Q000002:abnormalities / Q000378:metabolism; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005838:Genotype; D034381:Hearing Loss / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D007150:Immunohistochemistry; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000378:metabolism; D018993:Myelin P0 Protein / Q000378:metabolism; D012697:Serine Endopeptidases / Q000172:deficiency* / Q000235:genetics; D016708:Synaptophysin / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism; D013974:Thyroxine / Q000097:blood
chemical_list: D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D004676:Myelin Basic Protein; D018993:Myelin P0 Protein; D016708:Synaptophysin; D037042:Thyroid Hormone Receptors beta; D012697:Serine Endopeptidases; C055645:hepsin; D013974:Thyroxine