Molecular insights into MYO3A kinase domain variants explain variability in both severity and progression of DFNB30 hearing impairment

Abstract

Hereditary hearing impairment (HI) is a common disease with the highest incidence among sensory defects. Several genes have been identified to affect stereocilia structure causing HI, including the unconventional myosin3A. Interestingly, we noticed that variants in MYO3A gene have been previously found to cause variable HI onset and severity. Using clinical exome sequencing, we identified a novel pathogenic variant p.(Lys50Arg) in the MYO3A kinase domain (MYO3A-KD). Previous in vitro studies supported its damaging effect as a ‘kinase-dead’ mutant. We further analyzed this variation through molecular dynamics which predicts that changes in flexibility of MYO3A structure would influence the protein-ATP binding properties. This Lys50Arg mutation segregated with congenital profound non-syndromic HI. To better investigate this variability, we collected previously identified MYO3A-KDs variants, p.(Tyr129Cys), p.(His142Gln) and p.(Pro189Thr), and built both wild type and mutant 3 D MYO3A-KD models to assess their impact on the protein structure and function. Our results suggest that KD mutations could either cause a congenital profound form of HI, when particularly affecting the kinase activity and preventing the auto-phosphorylation of the motor, or a late onset and progressive form, when partially or completely inactivating the MYO3A protein. In conclusion, we report a novel pathogenic variant affecting the ATP-binding site within the MYO3A-KD causing congenital profound HI. Through computational approaches we provide a deeper understanding on the correlation between the effects of MYO3A-KD mutations and the variable hearing phenotypes. To the best of our knowledge this is the first study to correlate mutations’ genotypes with the variable phenotypes of DFNB30.

Communicated by Ramaswamy H. Sarma

Keywords:

• Hearing impairment severity
• pathogenic variant
• MYO3A Kinase domain
• molecular modelling

Acknowledgment

The authors would like to thank Dr. Mhamed Grati for his helpful comments.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval

This study was approved by the Regional Committee of the Protection of Persons, Sfax, Tunisia. Ethical committee number for the study: CPP SUD N°28/2019.

Additional information

Funding

This work was financially supported by the Ministry of Higher Education and Research of Tunisia (LR15CBS07, VRR projects).