Defects in
myosin VIIa, the PDZ-domain-containing
protein harmonin,
cadherin 23, protocadherin 15, and the putative scaffolding
protein sans, underlie five genetic forms of
Usher syndrome type I (USH1), the most frequent cause of hereditary
deafness-blindness in humans. Mice mutants defective for any of these
proteins have a severe
hearing impairment and display similar inner ear phenotypes characterized by the abnormal spreading of the sensory cells' stereocilia. These are highly specialized mechanoreceptive organelles derived from microvilli, that normally form a well-structured hair bundle at the apex of inner ear sensory cells. All the USH1
proteins, except sans, have been detected in the growing stereocilia. Moreover, biochemical studies have started to unravel the multiple direct molecular interactions between USH1
proteins. In particular, harmonin can bind to the other four USH1
proteins and to
F-actin. Finally, cell biology studies have provided the first insights into the functions of these
proteins, and revealed that
cadherin 23, and probably protocadherin 15 also, are associated with transient lateral links that interconnect growing stereocilia. These connectors play a critical role in the differentiating hair bundle.