MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15‐CD2 Isoform |
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| Authors: | M'hamed Grati Denise Yan Manmeet H. Raval Tom Walsh Qi Ma Imen Chakchouk Abhiraami Kannan‐Sundhari Rahul Mittal Saber Masmoudi Susan H. Blanton Mustafa Tekin Mary‐Claire King Christopher M. Yengo Xue Zhong Liu |
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| Affiliation: | 1. Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida;2. Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania;3. Departments of Medicine and Genome Sciences, University of Washington, Seattle, Washington;4. Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisie;5. Dr. John T. Macdonald Foundation, Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida;6. Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China |
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| Abstract: | ![]()
Hereditary hearing loss (HL) is characterized by both allelic and locus genetic heterogeneity. Both recessive and dominant forms of HL may be caused by different mutations in the same deafness gene. In a family with post‐lingual progressive non‐syndromic deafness, whole‐exome sequencing of genomic DNA from five hearing‐impaired relatives revealed a single variant, p.Gly488Glu (rs145970949:G>A) in MYO3A, co‐segregating with HL as an autosomal dominant trait. This amino acid change, predicted to be pathogenic, alters a highly conserved residue in the motor domain of MYO3A. The mutation severely alters the ATPase activity and motility of the protein in vitro, and the mutant protein fails to accumulate in the filopodia tips in COS7 cells. However, the mutant MYO3A was able to reach the tips of organotypic inner ear culture hair cell stereocilia, raising the possibility of a local effect on positioning of the mechanoelectrical transduction (MET) complex at the stereocilia tips. To address this hypothesis, we investigated the interaction of MYO3A with the cytosolic tail of the integral tip‐link protein protocadherin 15 (PCDH15), a core component of MET complex. Interestingly, we uncovered a novel interaction between MYO3A and PCDH15 shedding new light on the function of myosin IIIA at stereocilia tips. |
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| Keywords: | Dominant autosomal deafness MYO3A Protocadherin 15‐CD2 Ear sensory hair cells Mechanotransduction complex |
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