Usher syndrome: molecular links of pathogenesis, proteins and pathways

Abstract

Usher syndrome is the most common form of deaf-blindness. The syndrome is both clinically and genetically heterogeneous, and to date, eight causative genes have been identified. The proteins encoded by these genes are part of a dynamic protein complex that is present in hair cells of the inner ear and in photoreceptor cells of the retina. The localization of the Usher proteins and the phenotype in animal models indicate that the Usher protein complex is essential in the morphogenesis of the stereocilia bundle in hair cells and in the calycal processes of photoreceptor cells. In addition, the Usher proteins are important in the synaptic processes of both cell types. The association of other proteins with the complex indicates functional links to a number of basic cell-biological processes. Prominently present is the connection to the dynamics of the actin cytoskeleton, involved in cellular morphology, cell polarity and cell-cell interactions. The Usher protein complex can also be linked to the cadherins/catenins in the adherens junction-associated protein complexes, suggesting a role in cell polarity and tissue organization. A third link can be established to the integrin transmembrane signaling network. The Usher interactome, as outlined in this review, participates in pathways common in inner ear and retina that are disrupted in the Usher syndrome.

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder

“…37 Like nucleoredoxin, the Usher protein complex is an effector of b-catenin, and also affects neuronal morphogenesis and structural plasticity. 38 Usher syndrome can cause central nervous system structural changes 39 and psychosis, 40 and there is one report of increased incidence of bipolar disorder among adults with prelingual-onset nonsyndromic deafness, 41 but it is not known if any of those patients carried the 'whirler' mutation. Finally, SORCS2 maps to a region on chromosome 4p that has been widely linked to bipolar disorder 42 (Supplementary References).…”

The Kinetic Mechanism of Mouse Myosin VIIA

“…In the stereocilia myosin VIIa localizes to the actin bundles and forms the lateral and ankle links in between stereocilia along with its numerous binding partners e.g. vezatin and harmonin b and the cadherin/␣-catenin complex (49,50). It has been suggested that myosin VIIa is responsible for maintaining the tension by linking the stereocilial membrane to the actin core thus causing tension in membrane-bound elements such as transducer channels, the tip link and the lateral links.…”

Clarin-1, Encoded by the Usher Syndrome III Causative Gene, Forms a Membranous Microdomain

“…Increasing evidence suggests that products of Usher type I and II genes form large networks of interacting proteins, and that F-actin plays a major role in organizing these networks (reviewed in Refs. 2,9). The core of these networks is the Usher type IC gene product, Harmonin, which interacts directly with F-actin in vitro and stabilizes F-actin when it is expressed heterologously in HeLa cells (10).…”

“…Harmonins retain multiple PDZ domains dedicated to interacting with products of Usher type I and type II genes (reviewed in Refs. 2,9) and also serve as PDZ domainbased scaffolds to anchor Usher proteins to F-actin. A link between Usher gene products and actin-based organelles also has been established in vivo.…”