title: The effect of novel mutations on the structure and enzymatic activity of unconventional myosins associated with autosomal dominant non-syndromic hearing loss.
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.
authors: School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu, South Korea.
authors: Tae-Jun
authors: TJ
authors: Kwon
authors: School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu, South Korea.
authors: Se-Kyung
authors: SK
authors: Oh
authors: Soree Ear Clinic, Seoul, South Korea.
authors: Hong-Joon
authors: HJ
authors: Park
authors: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Osamu
authors: O
authors: Sato
authors: Centre for Molecular and Biomolecular Informatics, Radboudumc, Nijmegen, The Netherlands.
authors: Hanka
authors: H
authors: Venselaar
authors: Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Soo Young
authors: SY
authors: Choi
authors: Department of Otolaryngology, Fatima Hospital, Daegu, South Korea.
authors: SungHee
authors: S
authors: Kim
authors: Department of Otolaryngology, College of Medicine, Kyungpook National University, Daegu, South Korea.
authors: Kyu-Yup
authors: KY
authors: Lee
authors: Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
authors: Jinwoong
authors: J
authors: Bok
authors: Department of Otolaryngology, College of Medicine, Kyungpook National University, Daegu, South Korea.
authors: Sang-Heun
authors: SH
authors: Lee
authors: Centre for Molecular and Biomolecular Informatics, Radboudumc, Nijmegen, The Netherlands.
authors: Gert
authors: G
authors: Vriend
authors: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Mitsuo
authors: M
authors: Ikebe
authors: School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu, South Korea kimuk@knu.ac.kr.
authors: Un-Kyung
authors: UK
authors: Kim
authors: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea jychoi@yuhs.ac.
authors: Jae Young
authors: JY
authors: Choi
mesh_terms: D000199:Actins / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000595:Amino Acid Sequence; D005260:Female; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D024461:Myosin Type I / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011487:Protein Conformation
chemical_list: D000199:Actins; C062291:MYO1A protein, human; C089785:myosin VI; D000251:Adenosine Triphosphatases; D024461:Myosin Type I; D018995:Myosin Heavy Chains
keywords: ATPase; gene; mutation; myosin; protein structure