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

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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 - IG → 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 Glyl831Val mutation inhibits the power-stroke by reducing backbone flexibility and weakening the hydrophobic interactions necessary for signal transmission to the converter domain.

LanguageEnglish
Pages2382-2389
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Volume143
Issue number20
DOIs
Publication statusPublished - 15 Oct 2007
Externally publishedYes

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Functional Hearing Loss
Myosins
Mutation
Chromosomes
Deafness
Missense Mutation
Hydrophobic and Hydrophilic Interactions
Hearing Loss
Genes
Stroke
Head
Nonsyndromic Deafness
Proteins

Cite this

Kalay, E., Uzumcu, A., Krieger, E., Çaylan, R., Uyguner, O., Ulubil-Emiroglu, M., ... Kremer, H. (2007). MYO15A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation. American Journal of Medical Genetics, Part A, 143(20), 2382-2389. https://doi.org/10.1002/ajmg.a.31937
Kalay, Ersan ; Uzumcu, Abdullah ; Krieger, Elmar ; Çaylan, Refik ; Uyguner, Oya ; Ulubil-Emiroglu, Melike ; Erdol, Hidayet ; Kayserili, Hülya ; Hafiz, Gunter ; Başerer, Nermin ; Heister, Angelien J.G.M. ; Hennies, Hans C. ; Nürnberg, Peter ; Başaran, Seher ; Brunner, Han G. ; Cremers, Cor W.R.J. ; Karaguzel, Ahmet ; Wollnik, Bernd ; Kremer, Hannie. / MYO15A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation. In: American Journal of Medical Genetics, Part A. 2007 ; Vol. 143, No. 20. pp. 2382-2389.
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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 - IG → 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 Glyl831Val mutation inhibits the power-stroke by reducing backbone flexibility and weakening the hydrophobic interactions necessary for signal transmission to the converter domain.",
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Kalay, E, Uzumcu, A, Krieger, E, Çaylan, R, Uyguner, O, Ulubil-Emiroglu, M, Erdol, H, Kayserili, H, Hafiz, G, Başerer, N, Heister, AJGM, Hennies, HC, Nürnberg, P, Başaran, S, Brunner, HG, Cremers, CWRJ, Karaguzel, A, Wollnik, B & Kremer, H 2007, 'MYO15A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation', American Journal of Medical Genetics, Part A, vol. 143, no. 20, pp. 2382-2389. https://doi.org/10.1002/ajmg.a.31937

MYO15A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation. / Kalay, Ersan; Uzumcu, Abdullah; Krieger, Elmar; Çaylan, Refik; Uyguner, Oya; Ulubil-Emiroglu, Melike; Erdol, Hidayet; Kayserili, Hülya; Hafiz, Gunter; Başerer, Nermin; Heister, Angelien J.G.M.; Hennies, Hans C.; Nürnberg, Peter; Başaran, Seher; Brunner, Han G.; Cremers, Cor W.R.J.; Karaguzel, Ahmet; Wollnik, Bernd; Kremer, Hannie.

In: American Journal of Medical Genetics, Part A, Vol. 143, No. 20, 15.10.2007, p. 2382-2389.

Research output: Contribution to journalArticle

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AU - Kalay, Ersan

AU - Uzumcu, Abdullah

AU - Krieger, Elmar

AU - Çaylan, Refik

AU - Uyguner, Oya

AU - Ulubil-Emiroglu, Melike

AU - Erdol, Hidayet

AU - Kayserili, Hülya

AU - Hafiz, Gunter

AU - Başerer, Nermin

AU - Heister, Angelien J.G.M.

AU - Hennies, Hans C.

AU - Nürnberg, Peter

AU - Başaran, Seher

AU - Brunner, Han G.

AU - Cremers, Cor W.R.J.

AU - Karaguzel, Ahmet

AU - Wollnik, Bernd

AU - Kremer, Hannie

PY - 2007/10/15

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N2 - 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 - IG → 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 Glyl831Val mutation inhibits the power-stroke by reducing backbone flexibility and weakening the hydrophobic interactions necessary for signal transmission to the converter domain.

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KW - Deafness

KW - DFNB3

KW - Hearing loss

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T2 - American Journal of Medical Genetics, Part A

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