Myosin 15:Genetics, Pathology and Therapeutic Potential
Principal Investigator: Sally A Camper
Abstract: Abstract Hereditary inner ear disease is prevalent and has significant implications for quality of life. There is currently no available clinical cure for hereditary inner ear disease. The mouse serves as an ideal mammalian model for understanding genetic inner ear disease and for developing therapeutic measures. Mouse models have facilitated the discovery of genes that underlie hereditary disease in humans, have made it possible to study the role of these genes in inner ear development and function, and hold great promise as models for developing treatments for hereditary inner ear disease. This grant application builds on our discovery that mutations in the unconventional myosin gene, Myo15, are responsible for profound congenital deafness and vestibular dysfunction in two spontaneous mouse mutants: shaker 2 and shaker 2J, and in humans with DFNB3. We used these mouse models to demonstrate the long-term structural and functional phenotypic correction of deafness with a transgene expressing Myo15. We characterized the development of pathology in Myo15, Myo6, Myo7a, pirouette, and whirlin deficient mutants, double heterozygotes and double mutants. Although there is no enhanced risk of age related hearing loss in double heterozygotes, these studies revealed unique functions of each myosin gene, and suggested the possibility that MYO15 has other functions besides transportation of whirlin to the stereocilia tips. We established adenoviral vectors for gene therapy and a database of genes exhibiting differential expression in the cochlea between weaning and adulthood in normal and Myo15 mutant mice. These studies laid a sound foundation for the goals of this grant. There are multiple isoforms of MYO15 that are generated by alternative splicing, including the presence or absence of a large proline-rich region N-terminal to the motor domain of MYO15. We hypothesize that this proline-rich region is important for protein-protein interactions necessary for hearing. We have generated a mouse model that recapitulates a human mutation in the proline-rich domain using knock-in technology. These mutants have profound congenital deafness, hair bundle pathology that is distinct from shaker 2 and shaker 2J mice, and apparently normal vestibular function. We propose a structure-function analysis that will reveal the importance of MYO15 isoforms in the development and function of the cochlea using mutant alleles, cell culture and cochlear explant assays. We will conduct a classical genetic analysis to evaluate interactions between mutant alleles and identify interacting proteins. Our investigative team has a track record for accomplishments resulting from cross-disciplinary collaboration, bringing together experts in otolaryngology, microscopy, physiology, and developmental genetics. This team will enable us to exploit the animal models fully to understand the mechanisms of inner ear disease and has the potential to identify novel genes essential for normal hearing.
Funding Period: 2001-08-01 - 2014-08-31
more information: NIH RePORT
- Manipulating gene expression in the mature inner earMark A Crumling
Kresge Hearing Research Institute, The University of Michigan, MSRB III Room 9303, Ann Arbor, MI 48109 0648, USA
Brain Res 1091:265-9. 2006....
- p27(Kip1) deficiency causes organ of Corti pathology and hearing lossSho Kanzaki
Kresge Hearing Research Institute, The University of Michigan Medical School, MSRB III Room 9303, 1150 West Medical Center Drive, Ann Arbor, MI 48109 0648, USA
Hear Res 214:28-36. 2006..Manipulations to regulate the time and place of p27 inhibition will be necessary for inducing functionally useful hair cell regeneration...
- Transgene correction maintains normal cochlear structure and function in 6-month-old Myo15a mutant miceSho Kanzaki
Kresge Hearing Research Institute, University of Michigan, MSRB III Room 9303, Ann Arbor, MI 48109 0648, USA
Hear Res 214:37-44. 2006..In addition, excess Myo15a expression has no physiologically significant protective or deleterious effects on hearing of normal mice, suggesting that the dosage of Myo15a may not be problematic for gene therapy...
- The role of bone morphogenetic protein 4 in inner ear development and functionMarsha N Blauwkamp
Cellular and Molecular Biology Program, 2966 Taubman Medical Library, University of Michigan, Ann Arbor, MI 48109 0619, USA
Hear Res 225:71-9. 2007..Thus Bmp4(+/-) mice have structural and functional deficits in the inner ear...
- Whirler mutant hair cells have less severe pathology than shaker 2 or double mutantsMirna Mustapha
Department of Human Genetics, University of Michigan, 4909 Buhl Building, 1241 East Catherine Street, Ann Arbor, MI 48109 0618, USA
J Assoc Res Otolaryngol 8:329-37. 2007..This suggests that MYOSIN XV may interact with other proteins besides WHIRLIN that are important for hair cell maturation...
- Dietary thyroid hormone replacement ameliorates hearing deficits in hypothyroid miceI Jill Karolyi
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109 0618, USA
Mamm Genome 18:596-608. 2007..We conclude that TH supplement administered during the critical period of hearing development in mice can prevent deafness associated with congenital hypothyroidism of heterogeneous genetic etiology...
- Deafness and permanently reduced potassium channel gene expression and function in hypothyroid Pit1dw mutantsMirna Mustapha
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109 5618, USA
J Neurosci 29:1212-23. 2009..In summary, we suggest that these defects in outer hair cell and strial cell function are important contributors to the hearing impairment in Pit1(dw) mice...
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