RESUMO
The motor protein myosin IIIA is critical for maintenance of normal hearing. Homozygosity and compound heterozygosity for loss-of-function mutations in MYO3A, which encodes myosin IIIA, are responsible for inherited human progressive hearing loss DFNB30. To further evaluate this hearing loss, we constructed a mouse model, Myo3a(KI/KI), that harbors the mutation equivalent to the nonsense allele responsible for the most severe human phenotype. Myo3a(KI/KI) mice were compared to their wild-type littermates. Myosin IIIA, with a unique N-terminal kinase domain and a C-terminal actin-binding domain, localizes to the tips of stereocilia in wild-type mice but is absent in the mutant. The phenotype of the Myo3a(KI/KI) mouse parallels the phenotype of human DFNB30. Hearing loss, as measured by auditory brainstem response, is reduced and progresses significantly with age. Vestibular function is normal. Outer hair cells of Myo3a(KI/KI) mice degenerate with age in a pattern consistent with their progressive hearing loss.
Assuntos
Modelos Animais de Doenças , Perda Auditiva/metabolismo , Camundongos , Cadeias Pesadas de Miosina/deficiência , Miosina Tipo III/deficiência , Fatores Etários , Animais , Sequência de Bases , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Cadeias Pesadas de Miosina/química , Cadeias Pesadas de Miosina/genética , Miosina Tipo III/química , Miosina Tipo III/genética , Estrutura Terciária de ProteínaRESUMO
Perception of sound is a fundamental role of the auditory system. Traveling with the force of their mechanical energy, sound waves are captured by the ear and activate the sensory pathway of this complex organ. The hair cells, specialized sensory cells within the inner ear, transmit the mechanical energy into electrical nerve stimuli that reach the brain. A large number of proteins are responsible for the overarching tasks required to maintain the complex mechanism of sound sensation. Many hearing disorders are due to single gene defects inherited in a Mendelian fashion, thus enabling clinical diagnostics. However, at the same time, hearing impairment is genetically heterogeneous, with both common and rare forms occurring due to mutations in over 100 genes. The crosstalk between human and mouse genetics has enabled comprehensive studies on gene identification and protein function, taking advantage of the tools animal models have to offer. The aim of the following review is to provide background and examples of human deafness genes and the discovery of their function in the auditory system.