Mice Deficient for the Type II Transmembrane Serine Protease, TMPRSS1/hepsin, Exhibit Profound Hearing Loss (original) (raw)
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The fundamental and medical impacts of recent progress in research on hereditary hearing loss
Human Molecular Genetics, 1998
What would define real progress in the field of deafness research in fundamental and medical terms? In fundamental terms, progress would be measured by an improvement in our knowledge of the development and physiology of the ear. In medical terms, progress would lead to the division of the broad category of hearing defects into distinct clinical entities or subclasses, the collection of epidemiological data, the creation of molecular diagnostic tests, the improvement of genetic counselling services and the development of new therapeutics. In this review, we will introduce some general considerations on hereditary hearing loss and on the structure and function of the ear, present the rapidly emerging data on the molecular basis of syndromic and non-syndromic forms of hearing loss and comment on relevant recent progress in this field of research. Generally speaking, the isolation of genes underlying hereditary hearing loss has, as yet, had little impact on our understanding of the biology of the ear, whereas it has made major contributions to the medical field, in particular due to the recognition of two genes, Cx26 and mitochondrial 12S rRNA, as frequently underlying cases of non-syndromic hearing impairment.
The Genetic Basis of Hearing Loss: Recent Advances and Future Prospects
International Journal of Head and Neck Surgery
Hearing loss (HL) is a common and complex condition that can occur at any age, be inherited or acquired, and is associated with a wide number of etiologies. HL is the most common sensory deficit in newborn children. In developed countries, genetic causes are considered the most frequent etiology of HL, and are estimated to account for 75% of the causes of HL. Current estimates suggest 1% of human genes (200-250 genes) are associated with genetic HL, and to date, more than 80 genes with over 1000 mutations and 140 loci have been identified associated with non-syndromic HL. The Online Mendelian Inheritance in Man reports more than 400 syndromes with HL. Syndromic and non-syndromic HL can be caused by different mutations within the same gene. Establishing the genetic cause of HL in prelingual children facilitates the medical course of action, rehabilitation choices and long term care in children. Patients with HL of undiagnosed etiology should be evaluated by a clinical geneticist and consider genetic testing as a part of their multidisciplinary evaluation.
From deafness genes to hearing mechanisms: harmony and counterpoint
Trends in molecular medicine, 2006
The study of hereditary hearing impairments provides a unique opportunity to deal with two objectives simultaneously: (i) identification of the causative genes and the underlying pathogenic process in each form of deafness; and (ii) elucidation of the molecular and cellular mechanisms of hearing. This review highlights the breakthroughs achieved during the past 12 years, with respect to their medical impacts and advances in basic scientific knowledge. To date, this research relies extensively on mouse models to study human forms of deafness. But, can mouse models sustain genetic approaches to study the physiology and pathophysiology of the auditory system and to develop and test drugs?
Human Mutation, 2008
Building on our discovery that mutations in the transmembrane serine protease, TMPRSS3, cause nonsyndromic deafness, we have investigated the contribution of other TMPRSS family members to the auditory function. To identify which of the 16 known TMPRSS genes had a strong likelihood of involvement in hearing function, three types of biological evidence were examined: 1) expression in inner ear tissues; 2) location in a genomic interval that contains a yet unidentified gene for deafness; and 3) evaluation of hearing status of any available Tmprss knockout mouse strains. This analysis demonstrated that, besides TMPRSS3, another TMPRSS gene was essential for hearing and, indeed, mice deficient for Hepsin (Hpn) also known as Tmprss1 exhibited profound hearing loss. In addition, TMPRSS2, TMPRSS5, and CORIN, also named TMPRSS10, showed strong likelihood of involvement based on their inner ear expression and mapping position within deafness loci PKSR7, DFNB24, and DFNB25, respectively. These four TMPRSS genes were then screened for mutations in affected members of the DFNB24 and DFNB25 deafness families, and in a cohort of 362 sporadic deaf cases. This large mutation screen revealed numerous novel sequence variations including three potential pathogenic mutations in the TMPRSS5 gene. The mutant forms of TMPRSS5 showed reduced or absent proteolytic activity. Subsequently, TMPRSS genes with evidence of involvement in deafness were further characterized, and their sites of expression were determined. Tmprss1, 3, and 5 proteins were detected in spiral ganglion neurons. Tmprss3 was also present in the organ of Corti. TMPRSS1 and 3 proteins appeared stably anchored to the endoplasmic reticulum membranes, whereas TMPRSS5 was also detected at the plasma membrane. Collectively, these results provide evidence that TMPRSS1 and TMPRSS3 play and TMPRSS5 may play important and specific roles in hearing. Hum Mutat 29(1), 130-141, 2008. r r 2007 Wiley-Liss, Inc.
Molecular genetics of nonsyndromic deafness
One in every 1,000 newborn suffers from congenital hearing impairment. More than 60% of the congenital cases are caused by genetic factors. In most cases, hearing loss is a multifactorial disorder caused by both genetic and environmental factors. Molecular genetics of deafness has experienced remarkable progress in the last decade. Genes responsible for hereditary hearing impairment are being mapped and cloned progressively. This review focuses on non-syndromic hearing loss, since the gene involved in this type of hearing loss have only recently begun to be identified.
Nonsyndromic Deafness -Molecular Update
In most cases, hearing loss is a disorder caused by both genetic and environmental factors. The molecular description of deafness has experienced remarkable progress in the last decade, and it is emerging from the use of contemporary methods of cell and molecular biology. Currently, through the application of clinical and molecular genetics it is possible to identify genes associated with inherited, nonsyndromic deafness, and balance dysfunctions of the human cochlea. This brief review provides insights into nonsyndromic hearing loss, since the identification of the molecular basis for the inner ear function provides the basis for developing rational new approaches to diagnosis, management and treatment of auditory and vestibular disorders.