Human Genetics

, Volume 115, Issue 2, pp 149–156 | Cite as

Identification and molecular modelling of a mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11)

  • Mirjam W. J. Luijendijk
  • Erwin van Wijk
  • Anne M. L. C. Bischoff
  • Elmar Krieger
  • Patrick L. M. Huygen
  • Ronald J. E. Pennings
  • Han G. Brunner
  • Cor W. R. J. Cremers
  • Frans P. M. Cremers
  • Hannie KremerEmail author
Original Investigation


Myosin VIIA is an unconventional myosin that has been implicated in Usher syndrome type 1B, atypical Usher syndrome, non-syndromic autosomal recessive hearing impairment (DFNB2) and autosomal dominant hearing impairment (DFNA11). Here, we present a family with non-syndromic autosomal dominant hearing impairment that clinically resembles the previously published DFNA11 family. The affected family members show a flat audiogram at young ages and only modest progression, most clearly at the high frequencies. In addition, they suffer from minor vestibular symptoms. Linkage analysis yielded a maximum two-point lodscore of 3.43 for marker D11S937 located within 1 cM of the myosin VIIA gene. The myosin VIIA gene was sequenced and 11 nucleotide variations were found. Ten nucleotide changes represent benign intronic variants, silent exon mutations or non-pathologic amino acid substitutions. One variant, a c.1373A→T transversion that is heterozygously present in all affected family members and absent in 300 healthy individuals, is predicted to result in an Asn458Ile amino acid substitution. Asn458 is located in a region of the myosin VIIA motor domain that is highly conserved in different classes of myosins and in myosins of different species. To evaluate whether the Asn458Ile mutation was indeed responsible for the hearing impairment, a molecular model of myosin VIIA was built based on the known structure of the myosin II heavy chain from Dictyostelium discoideum. In this model, conformational changes in the protein caused by the amino acid substitution Asn458Ile are predicted to disrupt ATP/ADP binding and impair the myosin power-stroke, which would have a severe effect on the function of the myosin VIIA protein.


Hair Cell Hearing Impairment Myosin Head Aberrant Protein Usher Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This project has been supported by the Foundation “De Drie Lichten” in The Netherlands, the Heinsius-Houbolt Foundation, the Nijmegen ORL Research Foundation and ZonMW AGIKO-grant 920-03-222. We thank Henriëtte Weekamp for her contribution in gathering the patient material, and Prof. Dr. J.R.M. Cruysberg for performing the ophthalmological examination of the patients.


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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Mirjam W. J. Luijendijk
    • 1
  • Erwin van Wijk
    • 2
  • Anne M. L. C. Bischoff
    • 2
  • Elmar Krieger
    • 3
  • Patrick L. M. Huygen
    • 2
  • Ronald J. E. Pennings
    • 2
  • Han G. Brunner
    • 1
  • Cor W. R. J. Cremers
    • 2
  • Frans P. M. Cremers
    • 1
  • Hannie Kremer
    • 2
    • 4
    Email author
  1. 1.Department of Human GeneticsUniversity Medical Center NijmegenNijmegenThe Netherlands
  2. 2.Department of OtorhinolaryngologyUniversity Medical Center NijmegenNijmegenThe Netherlands
  3. 3.Center for Molecular and Biomolecular InformaticsUniversity of NijmegenNijmegenThe Netherlands
  4. 4.Department of Human GeneticsUniversity Medical Center NijmegenNijmegenThe Netherlands

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