Zebrafish as a Model for Determining the Mechanisms Causing Deafness in MYH9-Related Disease

Abstract

Approximately 1 in 500 infants are diagnosed with hearing loss, and about half of these cases can be traced to genetic defects. Several hundred genes have been implicated in deafness, including MYH9, which codes for the conventional motor protein non-muscle myosin IIA (NMIIA). Mutations in MYH9 lead to syndromic MYH9-related diseases, which include deafness as a variable symptom, as well as non-syndromic autosomal deafness DFNA17. Despite its identification as a deafness gene, the functions of MYH9 in ear development and hearing remain unknown. To study this role, we will use zebrafish as a model. Zebrafish offer significant advantages including established genetic tools, large clutch sizes, and transparent embryos that develop externally. In addition, non-muscle myosin genes, including MYH9, are highly conserved from zebrafish to human, and the development and function of the vertebrate ear is also highly conserved. Zebrafish share many inner ear structures with humans including the sensory hair cells and cilia that make vestibular and auditory function possible. We hypothesize that myh9 plays a significant role in the developing zebrafish ear as suggested by myh9 knockdown experiments, which resulted in the phenotype of an abnormal number of otoliths. Because otoliths nucleate from precursor particles distributed in the fluid of the otic vesicle by motile cilia, we further hypothesize that the otolith phenotype is caused by a cilia defect. Our work has demonstrated that NMIIA colocalizes with ciliary basal bodies in the otic vesicle, suggesting a possible role in establishing basal body orientation.