Abstract

Twenty-eight million Americans suffer from hearing impairment. By age 80 about half the population has age-related hearing loss (presbycusis). While some degree of presbycusis can be ascribed to environmental exposures, a significant fraction is genetically determined. To understand the etiology of age-related hearing impairment it is necessary to understand both the molecular physiology of hearing and the molecular pathology of hearing loss. Identification and characterization of the genes that contribute to the hearing process are required to accomplish this goal. Mutations in the gamma-actin gene cause progressive sensorineural hearing loss that resembles presbycusis except for an earlier age of onset. It is somewhat surprising for mutations in such a ubiquitously expressed and highly conserved gene, to be associated with no other observed symptoms, suggesting very specific functions for gamma-actin in the ear. This study is designed to characterize those specific functions and to determine how known mutations in the gene encoding this protein affect its role in hearing. Both biochemical characterization and in vivo approaches will be used to achieve the goals. The specific role that gamma-actin plays in the ear will be examined using in situ localization of the protein and transient expression of the gamma-actin in cochlear and vestibular hair cells. Animal models with the mutations will be created and characterized. Studies of cell cultures expressing the normal and mutant proteins will be undertaken. A series of biochemical tests to determine the effect of each mutation on specific actin functions will examine the effect of the mutation on filament formation, cross-linking and myosin movement. Because we do not know how prevalent gamma-actin mutations are as the cause of hearing loss, additional families will be sought. These studies will help us to understand the role of gamma-actin in maintaining homeostasis in the ear and may thereby lead to a better understanding of the common and distressing phenomenon of age-related hearing impairment known as """"""""presbycusis"""""""".

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC004568-08
Application #
7578858
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (92))
Program Officer
Watson, Bracie
Project Start
2000-07-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2012-03-31
Support Year
8
Fiscal Year
2009
Total Cost
$332,067
Indirect Cost

  Institution

Name
Michigan State University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824

  Publications

Krey, Jocelyn F; Drummond, Meghan; Foster, Sarah et al. (2016) Annexin A5 is the Most Abundant Membrane-Associated Protein in Stereocilia but is Dispensable for Hair-Bundle Development and Function. Sci Rep 6:27221
Bonner, Joseph D; Fisher, Rachel; Klein, James et al. (2014) Pedigree structure and kinship measurements of a mid-Michigan community: a new North American population isolate identified. Hum Biol 86:59-68
Drummond, Meghan C; Friderici, Karen H (2013) A novel actin mRNA splice variant regulates ACTG1 expression. PLoS Genet 9:e1003743
Drummond, Meghan C; Belyantseva, Inna A; Friderici, Karen H et al. (2012) Actin in hair cells and hearing loss. Hear Res 288:89-99
Bergeron, Sarah E; Zhu, Mei; Thiem, Suzanne M et al. (2010) Ion-dependent polymerization differences between mammalian beta- and gamma-nonmuscle actin isoforms. J Biol Chem 285:16087-95
Wilch, E; Azaiez, H; Fisher, R A et al. (2010) A novel DFNB1 deletion allele supports the existence of a distant cis-regulatory region that controls GJB2 and GJB6 expression. Clin Genet 78:267-74
Belyantseva, Inna A; Perrin, Benjamin J; Sonnemann, Kevin J et al. (2009) Gamma-actin is required for cytoskeletal maintenance but not development. Proc Natl Acad Sci U S A 106:9703-8
Bryan, Keith E; Wen, Kuo-Kuang; Zhu, Mei et al. (2006) Effects of human deafness gamma-actin mutations (DFNA20/26) on actin function. J Biol Chem 281:20129-39
Wilch, Ellen; Zhu, Mei; Burkhart, Kirk B et al. (2006) Expression of GJB2 and GJB6 is reduced in a novel DFNB1 allele. Am J Hum Genet 79:174-9
Zhu, M; Yang, T; Wei, S et al. (2003) Mutations in the gamma-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26). Am J Hum Genet 73:1082-91

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