Mutant alleles of mammalian myosin XVA cause profound congenital deafness DFNB3. In humans worldwide, mutations of MYO15A apepars to be the third most common mutated gene associated with deafness. Myosins are actin based molecular motors that have a conserved head (motor) and neck (light chain binding motifs) and highly divergent tail domains. The MYO15A tail contains several motifs that are candidates for protein interaction motifs. To date, isoform 1 of myosin XVa is the largest of all reported vertebrate myosins. The N-terminus of myosin XVa is composed of 1,220 residues. We previously demonstrated that isoform 1 is necessary for hearing (Nal et al., 2007). As a collaboration with extramural scientists, a mouse model has been developed that has a defective amino terminus which recapitulates the human phenotype (unpublished data). The identification of proteins that functionally interact with MYO15 may provide a means of determining the role of MYO15A in the auditory system. In addition, interacting proteins are themselves likely to play crucial roles in hearing and would be strong candidates for proteins encoded by other deafness loci. We are therefore using a yeast two hybrid system and MS screens to identify proteins that interact with the myosin XVA. Genes that encode poteins that interact with myosin XVA from these two screens will be further examined for biological relevance. Whirlin is one such partner of the tail domain of myosin XVa and is necessary for stereocilia elongation and staircase formation (Belyantseva et al. 2005). We are also characterizing the biophysical properties of myosin XVa.

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Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2011
Total Cost
$1,119,944
Indirect Cost
Name
National Institute on Deafness and Other Communication Disorders
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Dewey, James B; Xia, Anping; Müller, Ulrich et al. (2018) Mammalian Auditory Hair Cell Bundle Stiffness Affects Frequency Tuning by Increasing Coupling along the Length of the Cochlea. Cell Rep 23:2915-2927
Ballesteros, Angela; Fenollar-Ferrer, Cristina; Swartz, Kenton Jon (2018) Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins. Elife 7:
Imtiaz, Ayesha; Belyantseva, Inna A; Beirl, Alisha J et al. (2018) CDC14A phosphatase is essential for hearing and male fertility in mouse and human. Hum Mol Genet 27:780-798
Melli, Luca; Billington, Neil; Sun, Sara A et al. (2018) Bipolar filaments of human nonmuscle myosin 2-A and 2-B have distinct motile and mechanical properties. Elife 7:
Bird, Jonathan E; Barzik, Melanie; Drummond, Meghan C et al. (2017) Harnessing molecular motors for nanoscale pulldown in live cells. Mol Biol Cell 28:463-475
Mauriac, Stephanie A; Hien, Yeri E; Bird, Jonathan E et al. (2017) Defective Gpsm2/G?i3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome. Nat Commun 8:14907
Naz, Sadaf; Imtiaz, Ayesha; Mujtaba, Ghulam et al. (2017) Genetic causes of moderate to severe hearing loss point to modifiers. Clin Genet 91:589-598
Rehman, A U; Friedman, T B; Griffith, A J (2017) Unresolved questions regarding human hereditary deafness. Oral Dis 23:551-558
Faridi, R; Rehman, A U; Morell, R J et al. (2017) Mutations of SGO2 and CLDN14 collectively cause coincidental Perrault syndrome. Clin Genet 91:328-332
Belyantseva, Inna A (2016) Helios(®) Gene Gun-Mediated Transfection of the Inner Ear Sensory Epithelium: Recent Updates. Methods Mol Biol 1427:3-26

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