Disease relevance of USH2A

• Usher syndrome type IIa (USH2A) combines moderate to severe congenital hearing impairment and retinitis pigmentosa [1].
• The ongoing studies of myosin-VIIa, the USH2A protein, and the yet to be identified proteins encoded by the other USH genes will advance understanding of the Usher syndromes and contribute to the development of effective therapies [2].
• Patients with USH1 have severe to profound congenital hearing impairment, vestibular dysfunction, and retinal degeneration beginning in childhood, while those with USH2 have moderate to severe hearing impairment, normal vestibular function, and later onset of retinal degeneration [2].
• Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells [3].
• Inhibitory effects of cytomegalovirus proteins US2 and US11 point to contributions from direct priming and cross-priming in induction of vaccinia virus-specific CD8(+) T cells [4].

Psychiatry related information on USH2A

• Borderline mental retardation, depression or bipolar affective disorder were observed in 16.7% of US1 and 33.3% of US2 patients [5].

High impact information on USH2A

• Thus, US2 may allow HCMV-infected macrophages to remain relatively 'invisible' to CD4+ T cells, a property that would be important after virus reactivation [3].
• Here, we show that the HCMV protein US2 causes degradation of two essential proteins in the MHC class II antigen presentation pathway: HLA-DR-alpha and DM-alpha [3].
• US2- and US11-mediated subversion of ER dislocation ensures proteasomal degradation of class I MHC molecules and presumably allows HCMV to avoid recognition by cytotoxic T cells, whilst providing insight into general aspects of ER-associated degradation (ERAD) which is used by eukaryotic cells to purge their ER of defective proteins [6].
• The USH2A gene encodes a protein with a predicted size of 171.5 kilodaltons that has laminin epidermal growth factor and fibronectin type III motifs; these motifs are most commonly observed in proteins comprising components of the basal lamina and extracellular matrixes and in cell adhesion molecules [7].
• Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa [7].

Chemical compound and disease context of USH2A

• A heterozygous sequence variant changing a glycine to arginine at codon 178 was found in one Usher syndrome type II (USH2) patient, while the other USH2 patients did not show any coding sequence variant [8].

Biological context of USH2A

• MYO7A is on chromosome region 11q13 and USH2A is on 1q41 [2].
• The phenotype resulting from MYO7A and USH2A mutations is variable [2].
• METHODS: We performed SSCP screening of MYO7A in 12 unrelated patients suffering from Usher syndrome type 1 (USH1) and USH2A in 28 unrelated patients affected by Usher syndrome type 2 (USH2) [9].
• Three clinical types are known (USH1, USH2 and USH3), and there is an extensive genetic heterogeneity, with at least ten genes implicated [10].
• The presence of pathogenic mutations in the novel exons indicates that at least one of the putative long isoforms of the USH2A protein plays a role in both hearing and vision [11].

Anatomical context of USH2A

• USH2A encodes usherin, which was previously defined as a basement membrane protein [1].
• In the retina, the co-expression of all USH1 and USH2 proteins at the synapse of photoreceptor cells indicates that they are organized in an USH protein network there [12].
• The mouse and rat genes, similar to human USH2A, are expressed primarily in retina and cochlea [13].
• Usherin, the defective protein in Usher syndrome type IIA, is likely to be a component of interstereocilia ankle links in the inner ear sensory cells [1].
• Expression of US2 in cells reduced or abolished their ability to present antigen to CD4+ T lymphocytes [3].

Associations of USH2A with chemical compounds

• We pinpoint these interactions to interactions between the PDZ1 domain of harmonin and the PDZ-binding motifs at the C-termini of the USH2 proteins and NBC3 [14].
• The unique short gene product US2 is a 199-amino acid type I endoplasmic reticulum glycoprotein that modulates surface expression of class I MHC products by targeting class I heavy chains for dislocation from the endoplasmic reticulum to the cytosol, where they undergo proteasomal degradation [15].
• Although ubiquitin conjugation may occur on the cytosolic tail of the class I MHC molecule, replacement of lysines in the cytosolic tail of heavy chains with arginine does not prevent their degradation by US2 [16].
• The lysine-less class I molecules could no longer be dislocated by US2 despite the fact that the interaction between the two proteins was maintained [17].
• Furthermore, site-directed mutagenesis of the US2 cytoplasmic tail revealed that the most critical residues for class I-induced destruction, cysteine 187, serine 190, tryptophan 193, and phenylalanine 196, occurs every third residue [15].

Other interactions of USH2A

• In addition, two USH2 genes and one USH3A gene have been identified [12].
• In contrast, the molecular pathogenesis of USH2A, which is owing to a defect of a novel extracellular matrix protein, is likely to be different from that of USH1 [18].
• METHODS: Three siblings with USH2C and 14 patients with USH2A were studied [19].
• Only 19 (6%) patients were found to have sequence changes in RHO, RDS, CRB1, or USH2A, 2 of which were thought to be disease-causing [20].
• The gene for transforming growth factor beta 2 (TGFB2) and the gene for the homeodomain box (HLX1) are both eliminated as candidates for USH2A, by virtue of their localization outside these flanking markers [21].

Analytical, diagnostic and therapeutic context of USH2A

• With in situ hybridization, we compared the cellular expression of the USH2A gene in rat, mouse, and human retinas [13].
• We analysed 35 British and one Pakistani Usher type II families with at least one affected member, for sequence changes in the 20 translated exons of the USH2A gene, using heteroduplex analysis and sequencing [22].
• Gene mapping of Usher syndrome type IIa: localization of the gene to a 2.1-cM segment on chromosome 1q41 [21].
• We studied the effect of US2 on surface expression of individual class I locus products using flow cytometry [23].
• Indirect immunofluorescence studies localized the US2 protein in the cytoplasm and as discrete granules at late times post-infection within and at the periphery of the nucleus, and nuclear fractionation studies showed that the protein was partially associated with the nuclear matrix of infected cells [24].

References