title: MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform.
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.
authors: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida.
authors: M'hamed
authors: M
authors: Grati
authors: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida.
authors: Denise
authors: D
authors: Yan
authors: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors: Manmeet H
authors: MH
authors: Raval
authors: Departments of Medicine and Genome Sciences, University of Washington, Seattle, Washington.
authors: Tom
authors: T
authors: Walsh
authors: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida.
authors: Qi
authors: Q
authors: Ma
authors: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida.|Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisie.
authors: Imen
authors: I
authors: Chakchouk
authors: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida.
authors: Abhiraami
authors: A
authors: Kannan-Sundhari
authors: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida.
authors: Rahul
authors: R
authors: Mittal
authors: Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisie.
authors: Saber
authors: S
authors: Masmoudi
authors: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida.|Dr. John T. Macdonald Foundation, Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida.
authors: Susan H
authors: SH
authors: Blanton
authors: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida.|Dr. John T. Macdonald Foundation, Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida.
authors: Mustafa
authors: M
authors: Tekin
authors: Departments of Medicine and Genome Sciences, University of Washington, Seattle, Washington.
authors: Mary-Claire
authors: MC
authors: King
authors: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors: Christopher M
authors: CM
authors: Yengo
authors: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida.|Dr. John T. Macdonald Foundation, Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida.|Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors: Xue Zhong
authors: XZ
authors: Liu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D003638:Deafness / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006199:Hair Cells, Auditory, Inner / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism*; D025102:Myosin Type III / Q000235:genetics* / Q000378:metabolism*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: C498835:CDHR15, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; C491724:MYO3A protein, human; D025102:Myosin Type III; D018995:Myosin Heavy Chains
keywords: Dominant autosomal deafness; Ear sensory hair cells; MYO3A; Mechanotransduction complex; Protocadherin 15-CD2