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Gene Review

USH2A  -  Usher syndrome 2A (autosomal recessive, mild)

Homo sapiens

Synonyms: RP39, US2, USH2, Usher syndrome type IIa protein, Usher syndrome type-2A protein, ...
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Disease relevance of USH2A


Psychiatry related information on USH2A


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


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


  1. 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. Adato, A., Lefèvre, G., Delprat, B., Michel, V., Michalski, N., Chardenoux, S., Weil, D., El-Amraoui, A., Petit, C. Hum. Mol. Genet. (2005) [Pubmed]
  2. The usher syndromes. Keats, B.J., Corey, D.P. Am. J. Med. Genet. (1999) [Pubmed]
  3. Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells. Tomazin, R., Boname, J., Hegde, N.R., Lewinsohn, D.M., Altschuler, Y., Jones, T.R., Cresswell, P., Nelson, J.A., Riddell, S.R., Johnson, D.C. Nat. Med. (1999) [Pubmed]
  4. 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. Basta, S., Chen, W., Bennink, J.R., Yewdell, J.W. J. Immunol. (2002) [Pubmed]
  5. Neuroradiology and clinical aspects of Usher syndrome. Tamayo, M.L., Maldonado, C., Plaza, S.L., Alvira, G.M., Tamayo, G.E., Zambrano, M., Frias, J.L., Bernal, J.E. Clin. Genet. (1996) [Pubmed]
  6. Antigen presentation and the ubiquitin-proteasome system in host-pathogen interactions. Loureiro, J., Ploegh, H.L. Adv. Immunol. (2006) [Pubmed]
  7. Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa. Eudy, J.D., Weston, M.D., Yao, S., Hoover, D.M., Rehm, H.L., Ma-Edmonds, M., Yan, D., Ahmad, I., Cheng, J.J., Ayuso, C., Cremers, C., Davenport, S., Moller, C., Talmadge, C.B., Beisel, K.W., Tamayo, M., Morton, C.C., Swaroop, A., Kimberling, W.J., Sumegi, J. Science (1998) [Pubmed]
  8. Analysis of phosducin as a candidate gene for retinopathies. Ara-Iwata, F., Jacobson, S.G., Gass, J.D., Hotta, Y., Fujiki, K., Hayakawa, M., Inana, G. Ophthalmic Genet. (1996) [Pubmed]
  9. Novel mutations in MYO7A and USH2A in Usher syndrome. Maubaret, C., Griffoin, J.M., Arnaud, B., Hamel, C. Ophthalmic Genet. (2005) [Pubmed]
  10. Mutations in myosin VIIA (MYO7A) and usherin (USH2A) in Spanish patients with Usher syndrome types I and II, respectively. Nájera, C., Beneyto, M., Blanca, J., Aller, E., Fontcuberta, A., Millán, J.M., Ayuso, C. Hum. Mutat. (2002) [Pubmed]
  11. Identification of 51 novel exons of the Usher syndrome type 2A (USH2A) gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type II. van Wijk, E., Pennings, R.J., te Brinke, H., Claassen, A., Yntema, H.G., Hoefsloot, L.H., Cremers, F.P., Cremers, C.W., Kremer, H. Am. J. Hum. Genet. (2004) [Pubmed]
  12. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Reiners, J., Nagel-Wolfrum, K., Jürgens, K., Märker, T., Wolfrum, U. Exp. Eye Res. (2006) [Pubmed]
  13. Identification of the mouse and rat orthologs of the gene mutated in Usher syndrome type IIA and the cellular source of USH2A mRNA in retina, a target tissue of the disease. Huang, D., Eudy, J.D., Uzvolgyi, E., Davis, J.R., Talmadge, C.B., Pretto, D., Weston, M.D., Lehman, J.E., Zhou, M., Seemayer, T.A., Ahmad, I., Kimberling, W.J., Sumegi, J. Genomics (2002) [Pubmed]
  14. Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2. Reiners, J., van Wijk, E., Märker, T., Zimmermann, U., Jürgens, K., te Brinke, H., Overlack, N., Roepman, R., Knipper, M., Kremer, H., Wolfrum, U. Hum. Mol. Genet. (2005) [Pubmed]
  15. A structural determinant of human cytomegalovirus US2 dictates the down-regulation of class I major histocompatibility molecules. Oresic, K., Noriega, V., Andrews, L., Tortorella, D. J. Biol. Chem. (2006) [Pubmed]
  16. Ubiquitinylation of the cytosolic domain of a type I membrane protein is not required to initiate its dislocation from the endoplasmic reticulum. Furman, M.H., Loureiro, J., Ploegh, H.L., Tortorella, D. J. Biol. Chem. (2003) [Pubmed]
  17. Ubiquitination of MHC Class I Heavy Chains Is Essential for Dislocation by Human Cytomegalovirus-encoded US2 but Not US11. Hassink, G.C., Barel, M.T., Van Voorden, S.B., Kikkert, M., Wiertz, E.J. J. Biol. Chem. (2006) [Pubmed]
  18. Usher syndrome: from genetics to pathogenesis. Petit, C. Annual review of genomics and human genetics. (2001) [Pubmed]
  19. Disease expression in Usher syndrome caused by VLGR1 gene mutation (USH2C) and comparison with USH2A phenotype. Schwartz, S.B., Aleman, T.S., Cideciyan, A.V., Windsor, E.A., Sumaroka, A., Roman, A.J., Rane, T., Smilko, E.E., Bennett, J., Stone, E.M., Kimberling, W.J., Liu, X.Z., Jacobson, S.G. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
  20. Utility of molecular testing for related retinal dystrophies. Mezer, E., Sutherland, J., Goei, S.L., Héon, E., Levin, A.V. Can. J. Ophthalmol. (2006) [Pubmed]
  21. Gene mapping of Usher syndrome type IIa: localization of the gene to a 2.1-cM segment on chromosome 1q41. Kimberling, W.J., Weston, M.D., Möller, C., van Aarem, A., Cremers, C.W., Sumegi, J., Ing, P.S., Connolly, C., Martini, A., Milani, M. Am. J. Hum. Genet. (1995) [Pubmed]
  22. Spectrum of mutations in USH2A in British patients with Usher syndrome type II. Leroy, B.P., Aragon-Martin, J.A., Weston, M.D., Bessant, D.A., Willis, C., Webster, A.R., Bird, A.C., Kimberling, W.J., Payne, A.M., Bhattacharya, S.S. Exp. Eye Res. (2001) [Pubmed]
  23. Human cytomegalovirus-encoded US2 differentially affects surface expression of MHC class I locus products and targets membrane-bound, but not soluble HLA-G1 for degradation. Barel, M.T., Ressing, M., Pizzato, N., van Leeuwen, D., Le Bouteiller, P., Lenfant, F., Wiertz, E.J. J. Immunol. (2003) [Pubmed]
  24. Characterization of the herpes simplex virus type 2 (HSV-2) US2 gene product and a US2-deficient HSV-2 mutant. Jiang, Y.M., Yamada, H., Goshima, F., Daikoku, T., Oshima, S., Wada, K., Nishiyama, Y. J. Gen. Virol. (1998) [Pubmed]
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