Current Therapeutic Strategies for Human Usher Syndrome

The human Usher syndrome (USH) is the most frequent cause of combined deafblindness in man. It is clinically and genetically heterogeneous and at least twelve chromosomal loci are assigned to three clinical USH types. USH1, USH2 and USH3 differ in the severity of the symptoms: hearing loss, balance problems and retinal degeneration namely retinitis pigmentosa (RP), as well as in the progression of the disease. Mutations in all USH genes result in similar symptoms. Nevertheless, molecular analyses of the corresponding gene products surprisingly revealed that USH proteins belong to diverse protein classes and families: myosin VIIa (USH1B) functions as a molecular motor; harmonin (USH1C), SANS (scaffold protein containing ankyrin repeats and SAM domain, USH1G) and whirlin (USH2D) are scaffold proteins; cadherin 23 (USH1D) and protocadherin 15 (USH1F) represent cell-cell adhesion proteins; USH2A isoform b (USH2A) and the largest receptor GPR98/VLGR1b (very large G-protein coupled receptor 1b, USH2C) with seven transmembrane folds and clarin-1 (USH3A) with four transmembrane domains are transmembrane proteins (Reiners et al. 2006, Ebermann et al., 2007). Protein interaction assays demonstrated that all USH proteins are part of protein networks present in the sensory cells of the inner ear and eye. The main organizers of the networks are the three scaffolds harmonin, SANS and whirlin. Alternative splicing further increases the complexity of the USH networks by the presence of various isoforms, mainly of the scaffold harmonin, but also