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MYO15A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation

✍ Scribed by Ersan Kalay; Abdullah Uzumcu; Elmar Krieger; Refik Çaylan; Oya Uyguner; Melike Ulubil-Emiroglu; Hidayet Erdol; Hülya Kayserili; Gunter Hafiz; Nermin Başerer; Angelien J.G.M. Heister; Hans C. Hennies; Peter Nürnberg; Seher Başaran; Han G. Brunner; Cor W.R.J. Cremers; Ahmet Karaguzel; Bernd Wollnik; Hannie Kremer

Publisher: John Wiley and Sons
Year: 2007
Tongue: English
Weight: 263 KB
Volume: 143A
Category: Article
ISSN: 1552-4825
DOI: 10.1002/ajmg.a.31937

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✦ Synopsis

Abstract

Myosin XVA is an unconventional myosin which has been implicated in autosomal recessive nonsyndromic hearing impairment (ARNSHI) in humans. In __Myo15__A 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. © 2007 Wiley‐Liss, Inc.

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