Usher syndrome represents the association of a hearing impairment with retinitis pigmentosa and is the most frequent cause of deaf-blindness in humans. It is inherited as an autosomal recessive trait which is clinically and genetically heterogeneous. Some patients show abnormal organization of microtubules in the axoneme of their photoreceptors cells (connecting cilium), nasal ciliar cells and sperm cells, as well as widespread degeneration of the organ of Corti. Usher syndrome type 1 (USH1) is characterized by a profound congenital sensorineural hearing loss, constant vestibular dysfunction and prepubertal onset of retinitis pigmentosa. Of three different genes responsible for USH1. USH1B maps to 11q13.5 (ref. 10) and accounts for about 75% of USH1 patients. The mouse deafness shaker-1 (sh1) mutation has been localized to the homologous murine region. Taking into account the cytoskeletal abnormalities in USH patients, the identification of a gene encoding an unconventional myosin as a candidate for shaker-1 (ref. 14) led us to consider the human homologue as a good candidate for the gene that is defective in USH1B. Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B. Two different premature stop codons, a six-base-pair deletion and two different missense mutations were detected in five unrelated families. In one of these families, the mutations were identified in both alleles. These mutations, which are located at the amino-terminal end of the motor domain of the protein, are likely to result in the absence of a functional protein. Thus USH1B appears as a primary cytoskeletal protein defect. These results implicate the genes encoding other unconventional myosins and their interacting proteins as candidates for other genetic forms of Usher syndrome.

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.

Genetic deafness is common, affecting about 1 in 2,000 births. Many of these show primary abnormalities of the sensory neuroepithelia of the inner ear, as do several hearing-impaired mouse mutants, suggesting that genes involved in sensory transduction could be affected. Here we report the identification of one such gene, the mouse shaker-1 (sh1) gene. Shaker-1 homozygotes show hyperactivity, head-tossing and circling due to vestibular dysfunction, together with typical neuroepithelial-type cochlear defects involving dysfunction and progressive degeneration of the organ of Corti. The sh1 gene encodes an unconventional myosin molecule of the type VII family. Three mutations are described, two mis-sense mutations and a splice acceptor site mutation, all in the region encoding the myosin head. The myosin type VII molecule encoded by sh1 is the first molecule to be identified that is known, by virtue of its mutations, to be involved in auditory transduction.

The whirler (wi) mutation on mouse Chromosome (Chr) 4 results in an autosomal recessive neuroepithelial deafness and vestibular dysfunction exhibited as a characteristic shaker-waltzer behavior (deafness, circling, and head-bobbing). We have constructed a genetic linkage map across the wi region in both an interspecific [(wi/wi x CAST/Ei)F1 x wi/wi] backcross (n = 817) and an intraspecific [(wi/wi x CBA/Ca)F1 x wi/wi)] backcross (n = 335). In the interspecific backcross, wi was found to be non-recombinant with Orm1, 0.12 cM distal of D4Mit87 and Ambp, and 0.12 cM proximal of CD301. In the intraspecific backcross, wi was found to be non-recombinant with Orm1 and D4Mit244, 0.3 cM distal of Mup1, and 0.6 cM proximal of Tnc. We also report a family from the interspecific backcross that shows evidence of multiple recombinations across the region of mouse Chr 4 around the wi locus. These rearrangements appear specific to both the region and the family.

Whirler (wi) mice display profound deafness and a head-tossing and circling phenotype, showing an autosomal recessive mode of inheritance. The wi mutation has been shown to map close to the Orm gene cluster on mouse Chromosome (Chr) 4. We have, therefore, investigated the Orm loci as candidates for the whirler gene. Detailed mapping and analysis of the Orm gene cluster in both normal and whirler mice indicates the presence of a <48-kb deletion in whirler mice that disrupts the Orm1 locus. The Orm1 locus is also deleted in the CE/J mouse strain, and we discuss the candidature of Orm1 for the whirler gene.