MYO3A Causes Human Dominant Deafness and Interacts With Protocadherin 15-CD2 Isoform

Hum Mutat. 2016 May;37(5):481-7. doi: 10.1002/humu.22961. Epub 2016 Feb 16.

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.

Keywords: Dominant autosomal deafness; Ear sensory hair cells; MYO3A; Mechanotransduction complex; Protocadherin 15-CD2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • COS Cells
  • Cadherins / metabolism*
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Chlorocebus aethiops
  • Deafness / genetics*
  • Deafness / metabolism
  • Female
  • Genetic Predisposition to Disease
  • Hair Cells, Auditory, Inner / cytology
  • Hair Cells, Auditory, Inner / metabolism
  • Humans
  • Male
  • Middle Aged
  • Myosin Heavy Chains / genetics*
  • Myosin Heavy Chains / metabolism*
  • Myosin Type III / genetics*
  • Myosin Type III / metabolism*
  • Pedigree
  • Polymorphism, Single Nucleotide*

Substances

  • Cadherins
  • PCDH15 protein, human
  • MYO3A protein, human
  • Myosin Type III
  • Myosin Heavy Chains