Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-Onset Progressive Hearing Loss.

Shin-Ichiro Oka,Shin-Ichiro Kitajiri,Shinya Morita,Shin-Ichi Usami,Shuji Izumi,Chie Oshikawa,Natsumi Uehara,Timothy F Day,Shin-Ya Nishio,Jun Nakayama,Nobuhiko Okamoto,Satoko Abe,Tetsuo Ikezono,Hideaki Moteki,Misako Hyogo,Maiko Miyagawa

doi:10.3390/genes11030273

Abstract

MYO6 is known as a genetic cause of autosomal dominant and autosomal recessive inherited hearing loss. In this study, to clarify the frequency and clinical characteristics of hearing loss caused by MYO6 gene mutations, a large-scale genetic analysis of Japanese patients with hearing loss was performed. By means of massively parallel DNA sequencing (MPS) using next-generation sequencing for 8074 Japanese families, we found 27 MYO6 variants in 33 families, 22 of which are novel. In total, 2.40% of autosomal dominant sensorineural hearing loss (ADSNHL) in families in this study (32 out of 1336) was found to be caused by MYO6 mutations. The present study clarified that most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age. The estimated hearing deterioration was found to be 0.57 dB per year; when restricted to change after 40 years of age, the deterioration speed was accelerated to 1.07 dB per year. To obtain supportive evidence for pathogenicity, variants identified in the patients were introduced to MYO6 cDNA by site-directed mutagenesis and overexpressed in epithelial cells. They were then assessed for their effects on espin1-induced microvilli formation. Cells with wildtype myosin 6 and espin1 co-expressed created long microvilli, while co-expression with mutant constructs resulted in severely shortened microvilli. In conclusion, the present data clearly showed that MYO6 is one of the genes to keep in mind with regard to ADSNHL, and the molecular characteristics of the identified gene variants suggest that a possible pathology seems to result from malformed stereocilia of the cochlear hair cells.

Highlights

Genetic etiology is the most common cause of sensorineural hearing loss (SNHL), with over 50%of congenital hearing loss attributed to genetic causes in the US [1], a figure that is likely similar in all industrialized nations
A total of 27 possibly disease-causing MYO6 candidate variants were identified from 32 autosomal dominant (AD) inherited families and a single proband known to be affected with unknown inheritance in a heterozygous states (Table 1)
All identified variants were confirmed by Sanger sequencing and the pathogenicity of these variants was interpreted in accordance with the ACMG guidelines [23]

Summary

Introduction

Genetic etiology is the most common cause of sensorineural hearing loss (SNHL), with over 50%of congenital hearing loss attributed to genetic causes in the US [1], a figure that is likely similar in all industrialized nations. Several myosin genes are known to cause both syndromic and non-syndromic hearing loss (MYO7A, DFNA11 [3]; DFNB2 [4]; Usher syndrome type 1B [5]; MYH9, DFNA17 [6]; MYH9-related disorder [7]; MYH14, DFNA4 [8]; peripheral neuropathy, myopathy, hoarseness, and hearing loss [9]; MYO6, DFNA22 [10], DFNB37 [11]; MYO3A, DFNB30 [12]; MYO15A, DFNB3 [13]). The human MYO6 gene is located on chromosome 6q13 and its gene mutations can cause either autosomal dominant (AD) inherited non-syndromic hearing loss (DFNA22) or autosomal recessive (AR). Inherited non-syndromic hearing loss (DFNB37), possibly reflecting differences in pathophysiology among the mutations. Myosin 6 is likely to be involved in the maintenance of stereocilia

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Discussion

Conclusion