The mouse Snell's waltzer deafness gene encodes an unconventional myosin required for structural integrity of inner ear hair cells

Abstract

The mouse represents an excellent model system for the study of genetic deafness in humans. Many mouse deafness mutants have been identified and the anatomy of the mouse and human ear is similar. Here we report the use of a positional cloning approach to identify the gene encoded by the mouse recessive deafness mutation, Snell's waltzer (sv). We show that sv encodes an unconventional myosin heavy chain, myosin VI, which is expressed within the sensory hair cells of the inner ear, and appears to be required for maintaining their structural integrity. The requirement for myosin VI in hearing makes this gene an excellent candidate for a human deafness disorder.

Myosin VI Regulates Endocytosis of the Cystic Fibrosis Transmembrane Conductance Regulator

“…6C). These data are in agreement with observations in the Snell's waltzer mice, which do not express myosin VI and have no defect in fluid-phase endocytosis (44,60,61).…”

“…Myosin VI is most likely to participate in the apical membrane endocytosis in epithelial cells because, unlike most myosins, it moves toward the F-actin minus end, which is oriented away from the plasma membrane (35)(36)(37)(38)(39)(40)(41)(42). Myosin VI is enriched in endocytic sites, including plasma membrane actin networks, where its distribution overlaps with that of clathrin and AP-2 (36,39,41,(43)(44)(45)(46). Recent evidence demonstrates that myosin VI regulates early steps of TfR endocytosis, including uptake of TfR into clathrin-coated pits and formation of clathrin-coated vesicles (36), as well as the later stages of TfR endocytosis, including movement of uncoated vesicles toward the early endosomes on actin filaments (41,47).…”

Parallel actin bundles and their multiple actin-bundling proteins

“…Villin is not present [35], but recently, some potentially novel isoforms of espin have been identified in hair cell stereocilia (JR Bartles, G Sekerkova, A Li, B Chen, K Vranich, E Mugnaini, LG Tilney, Mol Biol Cell 1998, 9 Suppl: 135a). Deafness mutations that give rise to defects in the organization or dimensions of the hair cell stereocilia have been mapped to genes that encode unconventional myosins VIIA [36,37], VI [38] and XV [39*,40]. Both myosins VIIA and VI have been localized to the cuticular plate, the specialized actin filament gel-containing counterpart to the brush border terminal web that is situated beneath hair cell stereocilia [34], and myosin VIIA has also been detected in the cross-links between adjacent stereocilia [41].…”

Auditory hair cell precursors immortalized from the mammalian inner ear

“…Myosin VIIa is also found in the entire hair cell body, but includes a uniform distribution along the stereocilia (Hasson et al 1997). Mutations in the Myo7a gene are responsible for syndromic and non-syndromic deafness both in mice (Gibson et al 1995) and in humans (Weil et al 1995;Liu et al 1997), whereas mutations of Myo6 produce genetic deafness in mice (Avraham et al 1995).…”