Genetic hearing impairment affects around 1 in every 2,000 births. The bulk (approximately 70%) of genetic deafness is non-syndromic, in which hearing impairment is not associated with any other abnormalities. Over 25 loci involved in non-syndromic deafness have been mapped and mutations in connexin 26 have been identified as a cause of non-sydromic deafness. One locus for non-syndromic recessive deafness, DFNB2 (ref. 4), has been localized to the same chromosomal region, 11q14, as one of the loci, USH1B, underlying the recessive deaf-blind syndrome. Usher syndrome type 1b, which is characterized by profound congenital sensorineural deafness, constant vestibular dysfunction and prepubertal onset of retinitis pigmentosa. Recently, it has been shown that a gene encoding an unconventional myosin, myosin VIIA, underlies the mouse recessive deafness mutation, shaker-1 (ref. 5) as well as Usher syndrome type 1b. Mice with shaker-1 demonstrate typical neuroepithelial defects manifested by hearing loss and vestibular dysfunction but no retinal pathology. Differences in retinal patterns of expression may account for the variance in phenotype between shaker-1 mice and Usher type 1 syndrome. Nevertheless, the expression of MYO7A in the neuroepithelium suggests that it should be considered a candidate for non-syndromic deafness in the human population. By screening families with non-syndromic deafness from China, we have identified two families carrying MYO7A mutations.

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Information from such a sequence analysis is a useful tool in the further interpretation of X-ray structures. It allows the position of crucial residues from other members of a superfamily to be determined within the framework provided by the known structures and the functional significance of conserved or mutated residues to be assessed.

Ark1p (actin regulating kinase 1) was identified as a yeast protein that binds to Sla2p, an evolutionarily conserved cortical actin cytoskeleton protein. Ark1p and a second yeast protein, Prk1p, contain NH2-terminal kinase domains that are 70% identical. Together with six other putative kinases from a number of organisms, these proteins define a new protein kinase family that we have named the Ark family.Lack of both Ark1p and Prk1p resulted in the formation of large cytoplasmic actin clumps and severe defects in cell growth. These defects were rescued by wild-type, but not by kinase-dead versions of the proteins. Elevated levels of either Ark1p or Prk1p caused a number of actin and cell morphological defects that were not observed when the kinase-dead versions were overexpressed instead. Ark1p and Prk1p were shown to localize to actin cortical patches, making these two kinases the first signaling proteins demonstrated to be patch components. These results suggest that Ark1p and Prk1p may be downstream effectors of signaling pathways that control actin patch organization and function. Furthermore, results of double-mutant analyses suggest that Ark1p and Prk1p function in overlapping but distinct pathways that regulate the cortical actin cytoskeleton.

Longstanding evidence supports a role for actin in endocytosis; an intact actin cytoskeleton is required for endocytosis in yeast, and drugs that inhibit actin polymerization inhibit endocytosis in both yeast and mammalian cells. The yeast Arp2/3 complex is required for the internalization step of endocytosis. In addition, some early endocytic events in mammalian cells are associated with the formation of actin tails similar to those generated by activated Arp2/3 complex. However, until now no Arp2/3 complex activator has been identified among proteins known to mediate early steps in endocytosis. Here we show that the yeast endocytic protein Pan1p binds to and activates the Arp2/3 complex. Genetic interactions between PAN1 and mutants of Arp2/3 subunits, or of the Arp2/3 activator LAS17, provide evidence for this activity in vivo. We suggest that Pan1p forms the core of an endocytic complex and physically couples actin polymerization nucleated by the Arp2/3 complex to the endocytic machinery, thus providing the forces necessary for endocytosis.