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.