Mutations in the MYO7A
have been reported to cause non-syndromic autosomal dominant hearing loss. Until now, only seven mutations in the MYO7A
were known to segregate with DFNA11. Five of the seven mutations were located in the motor domain of the myosin VIIA gene, including p.G722R, p.N458I, p.A230V, p.D218N and p.G671S 
. In the present study, we identified an eighth mutation in a family in which progressive non-syndromic autosomal dominant hearing loss segregates with the DFNA11 locus. Through linkage analysis, we successfully mapped the causative locus to chromosome 11 at 11q13.4–q14.1. Sequence analysis revealed that an Arg668His change in the myosin VIIA gene product leads to the hearing loss observed in the family we studied. All affected family members are heterozygous for this mutated locus. The missense mutation is located in the highly conserved motor domain of the myosin VIIA gene. The R668H residue was predicted by modeling to seriously disturb the function of the motor domain of the protein. In the actin-activated ATPase activity experiment, the rate of NADH oxidation by wild-type myosin VIIA activity was higher than by mutant myosin VIIA, indicating that the ATPase activity was significantly lowered in the mutant myosin VIIA.
Myosin VIIA is a mechanoenzyme that uses actin-activated ATP turnover to power interactions with actin filaments to produce force or drive directed movements 
. The human myosin VIIA heavy chain is composed of the N-terminal motor domain, a neck region with 5 IQ motifs, and a complex tail region. The activity of myosin VIIA is regulated by the interaction between the motor domain and the tip of the tail 
. The myosin VIIA motor is composed of a central core and extensions to this central core form the actin-binding site and the relay, converter and the lever-arm regions. In the human cochlea, myosin VIIA is involved in hair bundle morphogenesis and mechanotransduction 
. Five of the seven reported mutations are located in the motor domain, while two of these mutations are in the IQ motifs ().
Although molecular modeling demonstrates that all seven mutations would disable the function of myosin VIIA, only the p.R853C mutation in the IQ5 region was found to impair the calmodulin binding of myosin VIIA using an in vivo
functional assay 
. Using an NADH ATPase activity assay, we showed that the p.R668H mutation in the motor domain reduces the ATPase activity of myosin VIIA. When bound to ATP, the myosin VIIA head domain interacts with actin filaments to produce force- or drive-directed movements 
. It is strongly suggested that this actin-binding ability depends on the structural stability of the myosin VIIA active site in conjunction with both the lever arm and the actin-binding interface 
. Mutations in these sites may disrupt the link between the active site and the converter domain, in turn destroying the actin-binding efficiency of myosin VIIA. By pursuing the same activity experiment, another mutation p.R244P in the head motor of MYO7A
was also found to seriously destroy the function of myosin VIIA 
, which further explained the genotype and phenotype in mutations of MYO7A
and deafness. Today, the vast majority of mutations in the MYO7A
are associated with autosomal recessive hearing loss or Usher syndrome. Generally, affected patients have inherited mutations from both parents. The nature of these mutations, which often create premature stop codons and are supposed to undergo nonsense-mediated mRNA decay and rare functional studies suggest that these recessive mutations cause disease by loss-of-function. Assuming that the p.R668H protein is produced, then the mutant protein is assumed to be trafficked to the site of action, to bind to actin but to be unable to confer normal movement to the complex or is unable to reach an appropriate confirmation due to comprised ATPase function. Spatio-temporally accumulation of dysfunction myosin VIIA molecules at actin bundles might confer a dominant negative effect on wild-type myosin molecules. This hypothesis will be addressed in future experiments.