Mutant alleles of myosin XVA cause profound congenital deafness DFNB3. In humans worldwide, mutations of MYO15A are a common cause of nonsyndromic deafness (Rehman et al., 2016). Myosins are actin-activated molecular motors that have a conserved head (motor) and neck (light chain binding motifs) and highly divergent tail domains. The tail of MYO15A has several motifs that are candidates for protein interaction motifs. To date, isoform 1 of myosin XVa is the largest of all reported vertebrate myosins ( 400 kDa). The N-terminus of myosin XVa is composed of 1,220 residues and encoded by a single exon. 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 (Fang et al., 2015). The identification of proteins that functionally interact with MYO15 may provide a means of determining the various roles of MYO15A in the auditory system. In addition, interacting proteins are themselves likely to play crucial functions 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 continuing to characterize the biophysical properties of myosin XVa (Bird et al., 2014). The function of additional novel isoforms of MYO15A are also being investigated (Rehman et al., 2016). MYO15A appears to be a master regulator of stereocilia architecture as well as necessary for the lifelong of maintenance of stereocilia. In addition, we have been studying mouse models that have abnormal stereocilia rootlets and are deaf For example,TRIOBP-4 and TRIOBP-5 are necessary for rootlet formation. Rootlets provide bundle stiffness necessary for the detection of sound. Different splice isoforms of TRIOBP are necessary for building rootlets while others are necessary for maintaining rootlets longterm.

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Support Year
19
Fiscal Year
2016
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Name
Deafness & 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:
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
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
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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