Mutant alleles of mammalian myosin XVA cause profound congenital deafness DFNB3. In humans worldwide, mutations of MYO15A apepars to be a common mutated gene associated with nonsyndromic deafness. Myosins are actin-activated 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 Drs. Sally Camper and Gregory Frolenkov, a mouse model has been developed that has a defective amino terminus which recapitulates the human phenotype (unpublished data).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 and EPS8 are reported partners of the tail domain of myosin XVa and are necessary for stereocilia elongation and staircase formation (Belyantseva et al. 2005). As a collaboration with Dr. Sellers (NHLBI), we are characterizing the biophysical properties of myosin XVa.

Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2013
Total Cost
$1,167,404
Indirect Cost
Name
National Institute on Deafness and Other Communication Disorders
Department
Type
DUNS #
City
State
Country
Zip Code
Morozko, Eva L; Nishio, Ayako; Ingham, Neil J et al. (2015) ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells. Hum Mol Genet 24:609-24
Barzik, Melanie; McClain, Leslie M; Gupton, Stephanie L et al. (2014) Ena/VASP regulates mDia2-initiated filopodial length, dynamics, and function. Mol Biol Cell 25:2604-19
Bird, Jonathan E; Takagi, Yasuharu; Billington, Neil et al. (2014) Chaperone-enhanced purification of unconventional myosin 15, a molecular motor specialized for stereocilia protein trafficking. Proc Natl Acad Sci U S A 111:12390-5
Rehman, Atteeq U; Santos-Cortez, Regie Lyn P; Morell, Robert J et al. (2014) Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86. Am J Hum Genet 94:144-52
Indzhykulian, Artur A; Stepanyan, Ruben; Nelina, Anastasiia et al. (2013) Molecular remodeling of tip links underlies mechanosensory regeneration in auditory hair cells. PLoS Biol 11:e1001583
Nayak, Gowri; Lee, Sue I; Yousaf, Rizwan et al. (2013) Tricellulin deficiency affects tight junction architecture and cochlear hair cells. J Clin Invest 123:4036-49