RESUMEN
The whirler mouse mutant (wi) does not respond to sound stimuli, and detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs). BAC-mediated transgene correction of the mouse phenotype and mutation analysis identified the causative gene as encoding a novel PDZ protein called whirlin. The gene encoding whirlin also underlies the human autosomal recessive deafness locus DFNB31. In the mouse cochlea, whirlin is expressed in the sensory IHC and OHC stereocilia. Our findings suggest that this novel PDZ domain-containing molecule acts as an organizer of submembranous molecular complexes that control the coordinated actin polymerization and membrane growth of stereocilia.
Asunto(s)
Sordera/genética , Expresión Génica , Proteínas de la Membrana/genética , Proteínas/genética , Secuencia de Aminoácidos , Animales , Mapeo Cromosómico , Cilios/fisiología , Cilios/ultraestructura , Análisis Mutacional de ADN , ADN Complementario/genética , Genes Recesivos , Células Ciliadas Auditivas Internas/ultraestructura , Células Ciliadas Auditivas Externas/ultraestructura , Humanos , Proteínas de la Membrana/fisiología , Ratones , Ratones Mutantes , Ratones Transgénicos , Datos de Secuencia Molecular , Fenotipo , Proteínas/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Homología de Secuencia de Aminoácido , Especificidad de la EspecieRESUMEN
Otitis media is the most common cause of hearing impairment in children and is primarily characterized by inflammation of the middle ear mucosa. Yet nothing is known of the underlying genetic pathways predisposing to otitis media in the human population. Increasingly, large-scale mouse mutagenesis programs have undertaken systematic and genome-wide efforts to recover large numbers of novel mutations affecting a diverse array of phenotypic areas involved with genetic disease including deafness. As part of the UK mutagenesis program, we have identified a novel deaf mouse mutant, Jeff (Jf). Jeff maps to the distal region of mouse chromosome 17 and presents with fluid and pus in the middle ear cavity. Jeff mutants are 21% smaller than wild-type littermates, have a mild craniofacial abnormality, and have elevated hearing thresholds. Middle ear epithelia of Jeff mice show evidence of a chronic proliferative otitis media. The Jeff mutant should prove valuable in elucidating the underlying genetic pathways predisposing to otitis media.
Asunto(s)
Sordera/genética , Modelos Animales de Enfermedad , Ratones Mutantes/genética , Otitis Media con Derrame/genética , Proteínas/genética , Animales , Umbral Auditivo , Constitución Corporal , Mapeo Cromosómico , Enfermedad Crónica , Anomalías Craneofaciales/genética , Sordera/fisiopatología , Humanos , Ratones , Otitis Media con Derrame/patología , Otitis Media con Derrame/fisiopatología , SupuraciónRESUMEN
The systematic identification of the function of all the genes in the mammalian genome is one of the major scientific challenges for the 21st century. A comprehensive insight into mammalian gene function will illuminate our understanding of the genetic bases of disease. Mouse mutagenesis is a powerful tool for the study of mammalian gene function. Most recently, a number of approaches employing the chemical mutagen ethylnitrosourea (ENU) have been utilised by mouse geneticists to deliver a substantial new collection of mouse disease models. The growing mouse mutant archive provides a powerful resource for the identification of novel genes involved with human genetic disease.