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Open Biol. 2014 Jul;4(7). pii: 140107. doi: 10.1098/rsob.140107.

The effect of novel mutations on the structure and enzymatic activity of unconventional myosins associated with autosomal dominant non-syndromic hearing loss.

Author information

1
School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu, South Korea.
2
Soree Ear Clinic, Seoul, South Korea.
3
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
4
Centre for Molecular and Biomolecular Informatics, Radboudumc, Nijmegen, The Netherlands.
5
Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
6
Department of Otolaryngology, Fatima Hospital, Daegu, South Korea.
7
Department of Otolaryngology, College of Medicine, Kyungpook National University, Daegu, South Korea.
8
Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
9
School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu, South Korea kimuk@knu.ac.kr.
10
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea jychoi@yuhs.ac.

Abstract

Mutations in five unconventional myosin genes have been associated with genetic hearing loss (HL). These genes encode the motor proteins myosin IA, IIIA, VI, VIIA and XVA. To date, most mutations in myosin genes have been found in the Caucasian population. In addition, only a few functional studies have been performed on the previously reported myosin mutations. We performed screening and functional studies for mutations in the MYO1A and MYO6 genes in Korean cases of autosomal dominant non-syndromic HL. We identified four novel heterozygous mutations in MYO6. Three mutations (p.R825X, p.R991X and Q918fsX941) produce a premature truncation of the myosin VI protein. Another mutation, p.R205Q, was associated with diminished actin-activated ATPase activity and actin gliding velocity of myosin VI in an in vitro analysis. This finding is consistent with the results of protein modelling studies and corroborates the pathogenicity of this mutation in the MYO6 gene. One missense variant, p.R544W, was found in the MYO1A gene, and in silico analysis suggested that this variant has deleterious effects on protein function. This finding is consistent with the results of protein modelling studies and corroborates the pathogenic effect of this mutation in the MYO6 gene.

KEYWORDS:

ATPase; gene; mutation; myosin; protein structure

PMID:
25080041
PMCID:
PMC4118606
DOI:
10.1098/rsob.140107
[Indexed for MEDLINE]
Free PMC Article

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