Molecular Analysis of the Supramolecular Usher Protein Complex in the Retina

Abstract

Human Usher syndrome (USH) is the most common form of deaf-blindness and also the most frequent case of recessive retinitis pigmentosa. According to the degree of the clinical symptoms, three different types of the Usher syndrome are distinguished: USH1, USH2 and USH3 (Davenport and Omenn, 1977). USH is genetically heterogeneous with eleven chromosomal loci, which can be assigned to the three USH types (USH1A-G, USH2A-C, USH3A) (Petit, 2001). Out of these, USH1 is the most severe form, characterized by profound congenital deafness, constant vestibular dysfunction and prepubertal-onset retinitis pigmentosa. USH2 patients show a milder congenital deafness, a slightly later onset of retinitis pigmentosa and no vestibular dysfunction. The rarest Usher type 3 shows a late onset of retinitis pigmentosa and a progressing hearing loss. So far the different USH subtypes have been grouped into one disease basically on the same phenotype of the patients, although the clinical symptoms of the individual differ noticeably. The protein harmonin, responsible for USH1C, is of special interest, since it contains three PDZ domains, known for protein-protein interactions. We have gathered evidence that the different USH proteins are molecularly linked essentially via the scaffold protein harmonin. Harmonin interacts hereby not only with USH1 proteins, but also with USH2 proteins. Thus, this is the first evidence for a molecular linkage between USH1 and USH2, beyond the shared phenotype.