title: MYO15A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation.
abstract: Myosin XVA is an unconventional myosin which has been implicated in autosomal recessive nonsyndromic hearing impairment (ARNSHI) in humans. In Myo15A mouse models, vestibular dysfunction accompanies the autosomal recessive hearing loss. Genomewide homozygosity mapping and subsequent fine mapping in two Turkish families with ARNSHI revealed significant linkage to a critical interval harboring a known deafness gene MYO15A on chromosome 17p13.1-17q11.2. Subsequent sequencing of the MYO15A gene led to the identification of a novel missense mutation, c.5492G-->T (p.Gly1831Val) and a novel splice site mutation, c.8968-1G-->C. These mutations were not detected in additional 64 unrelated ARNSHI index patients and in 230 Turkish control chromosomes. Gly1831 is a conserved residue located in the motor domains of the different classes of myosins of different species. Molecular modeling of the motor head domain of the human myosin XVa protein suggests that the Gly1831Val mutation inhibits the powerstroke by reducing backbone flexibility and weakening the hydrophobic interactions necessary for signal transmission to the converter domain.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. ersankalay@hotmail.com
authors.forename: Ersan
authors.initials: E
authors.lastname: Kalay
authors.forename: Abdullah
authors.initials: A
authors.lastname: Uzumcu
authors.forename: Elmar
authors.initials: E
authors.lastname: Krieger
authors.forename: Refik
authors.initials: R
authors.lastname: Caylan
authors.forename: Oya
authors.initials: O
authors.lastname: Uyguner
authors.forename: Melike
authors.initials: M
authors.lastname: Ulubil-Emiroglu
authors.forename: Hidayet
authors.initials: H
authors.lastname: Erdol
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Gunter
authors.initials: G
authors.lastname: Hafiz
authors.forename: Nermin
authors.initials: N
authors.lastname: Başerer
authors.forename: Angelien J G M
authors.initials: AJ
authors.lastname: Heister
authors.forename: Hans C
authors.initials: HC
authors.lastname: Hennies
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Seher
authors.initials: S
authors.lastname: Başaran
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Cor W R J
authors.initials: CW
authors.lastname: Cremers
authors.forename: Ahmet
authors.initials: A
authors.lastname: Karaguzel
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D006239:Haplotypes; D034381:Hearing Loss / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009218:Myosins / Q000737:chemistry* / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D014421:Turkey; D014633:Valine / Q000235:genetics / Q000378:metabolism
chemical_list: C485245:MYO15A protein, human; D009218:Myosins; D014633:Valine