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Gene Review

ROR2  -  receptor tyrosine kinase-like orphan...

Homo sapiens

Synonyms: BDB, BDB1, NTRKR2, Neurotrophic tyrosine kinase, receptor-related 2, Tyrosine-protein kinase transmembrane receptor ROR2
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Disease relevance of ROR2

  • ROR2 mRNA was expressed in parathyroid, testis, uterus, and also in diffuse type gastric cancer with signet ring cell features [1].
  • Mutations of the former cause the nevoid basal cell carcinoma syndrome (NBCCS) while mutations in the ROR2 gene have been found both in Robinow syndrome and in brachydactyly type 1B (BDB1) [2].
  • Moreover, knocking out the mouse Ror2 gene causes mesomelic dwarfism in the homozygous state, with almost identical features to recessive Robinow syndrome [3].
  • Down-regulation of Ror2 expression in fully differentiated SaOS-2 osteosarcoma cells inhibited alkaline phosphatase activity [4].

High impact information on ROR2

  • Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B [5].
  • Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation that removes the tyrosine kinase domain and all subsequent 3' regions of the gene in 14 patients from 7 families from Oman [6].
  • The identification of mutations in three distinct domains (containing Frizzled-like, kringle and tyrosine kinase motifs) indicates that these are all essential for ROR2 function [6].
  • The BDB1 locus was previously mapped to chromosome 9q22 within an interval of 7.5 cM (refs 9,10) [5].
  • Heterozygous (presumed gain of function) mutations in ROR2 were previously shown to cause dominant brachydactyly type B (BDB; ref. 7). In contrast, Ror2-/- mice have a short-limbed phenotype that is more reminiscent of the mesomelic shortening observed in RRS [7].

Biological context of ROR2

  • The gene for the autosomal recessive form was identified as the ROR2 gene on chromosome 9q22 [8].
  • One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B [3].
  • SH2 binding site within the RORHC domain was conserved among vertebrate ROR2 orthologs, but not among vertebrate ROR1 orthologs [1].
  • Comparative genomics on ROR1 and ROR2 orthologs [1].
  • Here, comparative integromics analyses on ROR1 and ROR2 orthologs were performed by using bioinformatics [1].

Anatomical context of ROR2

  • ROR1 and ROR2 are the pharmacogenomics targets in the fields of stem cell biology and oncology [1].
  • Specifically, mutant alleles of ROR2 that are associated with RRS are retained within the ER, whereas wild-type and non-pathogenic alleles are exported to the plasma membrane [9].
  • While the CD4(+) T cells from SIV-infected RM showed a significant increase of the baseline and anti-TCR-mediated ROR2 transcription, SIV infection in SM led to substantially decreased anti-TCR-stimulated ROR2 transcription [10].
  • Interestingly, 9q22 harbors the ROR2 gene, which is required for growth plate development, and Xq24 was linked to short stature [11].
  • It was also found that the majority of cellular Dlxin-1 is retained in the membrane fractions of wild-type but not Ror2-/- mouse embryonic fibroblasts [12].

Associations of ROR2 with chemical compounds


Other interactions of ROR2

  • In addition, he has vertebral anomalies, brachymelia of the arms, and a ventricular septal defect-features that are reminiscent of Robinow syndrome, which has also been shown to be caused by mutations in ROR2 [19].
  • ROR2 promoter rather than ROR1 promoter was more evolutionarily conserved [1].
  • Mutation analysis of NOG and ROR2, the genes responsible for proximal symphalangism and brachydactyly type B, respectively, was negative [20].

Analytical, diagnostic and therapeutic context of ROR2


  1. Comparative genomics on ROR1 and ROR2 orthologs. Katoh, M., Katoh, M. Oncol. Rep. (2005) [Pubmed]
  2. Interstitial deletion of chromosome 9, int del(9)(9q22.31-q31.2), including the genes causing multiple basal cell nevus syndrome and Robinow/brachydactyly 1 syndrome. Olivieri, C., Maraschio, P., Caselli, D., Martini, C., Beluffi, G., Maserati, E., Danesino, C. Eur. J. Pediatr. (2003) [Pubmed]
  3. One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B. Afzal, A.R., Jeffery, S. Hum. Mutat. (2003) [Pubmed]
  4. The orphan receptor tyrosine kinase Ror2 promotes osteoblast differentiation and enhances ex vivo bone formation. Liu, Y., Bhat, R.A., Seestaller-Wehr, L.M., Fukayama, S., Mangine, A., Moran, R.A., Komm, B.S., Bodine, P.V., Billiard, J. Mol. Endocrinol. (2007) [Pubmed]
  5. Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B. Oldridge, M., Fortuna, A.M., Maringa, M., Propping, P., Mansour, S., Pollitt, C., DeChiara, T.M., Kimble, R.B., Valenzuela, D.M., Yancopoulos, G.D., Wilkie, A.O. Nat. Genet. (2000) [Pubmed]
  6. Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2. Afzal, A.R., Rajab, A., Fenske, C.D., Oldridge, M., Elanko, N., Ternes-Pereira, E., Tüysüz, B., Murday, V.A., Patton, M.A., Wilkie, A.O., Jeffery, S. Nat. Genet. (2000) [Pubmed]
  7. Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. van Bokhoven, H., Celli, J., Kayserili, H., van Beusekom, E., Balci, S., Brussel, W., Skovby, F., Kerr, B., Percin, E.F., Akarsu, N., Brunner, H.G. Nat. Genet. (2000) [Pubmed]
  8. Robinow syndrome. Patton, M.A., Afzal, A.R. J. Med. Genet. (2002) [Pubmed]
  9. ER-associated protein degradation is a common mechanism underpinning numerous monogenic diseases including Robinow syndrome. Chen, Y., Bellamy, W.P., Seabra, M.C., Field, M.C., Ali, B.R. Hum. Mol. Genet. (2005) [Pubmed]
  10. Identification of protein kinases dysregulated in CD4(+) T cells in pathogenic versus apathogenic simian immunodeficiency virus infection. Bostik, P., Wu, P., Dodd, G.L., Villinger, F., Mayne, A.E., Bostik, V., Grimm, B.D., Robinson, D., Kung, H.J., Ansari, A.A. J. Virol. (2001) [Pubmed]
  11. Genetic linkage of human height is confirmed to 9q22 and Xq24. Liu, Y.Z., Xiao, P., Guo, Y.F., Xiong, D.H., Zhao, L.J., Shen, H., Liu, Y.J., Dvornyk, V., Long, J.R., Deng, H.Y., Li, J.L., Recker, R.R., Deng, H.W. Hum. Genet. (2006) [Pubmed]
  12. The receptor tyrosine kinase Ror2 associates with the melanoma-associated antigen (MAGE) family protein Dlxin-1 and regulates its intracellular distribution. Matsuda, T., Suzuki, H., Oishi, I., Kani, S., Kuroda, Y., Komori, T., Sasaki, A., Watanabe, K., Minami, Y. J. Biol. Chem. (2003) [Pubmed]
  13. A novel family of cell surface receptors with tyrosine kinase-like domain. Masiakowski, P., Carroll, R.D. J. Biol. Chem. (1992) [Pubmed]
  14. Screening for and validated quantification of amphetamines and of amphetamine- and piperazine-derived designer drugs in human blood plasma by gas chromatography/mass spectrometry. Peters, F.T., Schaefer, S., Staack, R.F., Kraemer, T., Maurer, H.H. Journal of mass spectrometry : JMS. (2003) [Pubmed]
  15. Recent methods for assessing effectiveness of antihypertensive agents. Schneider, B.E., Littman, G.S., Walker, B.R. Clinical therapeutics. (1983) [Pubmed]
  16. A behavioral comparison of Nexus, cathinone, BDB, and MDA. Bronson, M.E., Jiang, W., DeRuiter, J., Clark, C.R. Pharmacol. Biochem. Behav. (1995) [Pubmed]
  17. Multiplex assay of amphetamine, methamphetamine, and ecstasy drug using CEDIA technology. Loor, R., Lingenfelter, C., Wason, P.P., Tang, K., Davoudzadeh, D. Journal of analytical toxicology. (2002) [Pubmed]
  18. Homodimerization of Ror2 tyrosine kinase receptor induces 14-3-3(beta) phosphorylation and promotes osteoblast differentiation and bone formation. Liu, Y., Ross, J.F., Bodine, P.V., Billiard, J. Mol. Endocrinol. (2007) [Pubmed]
  19. Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B. Schwabe, G.C., Tinschert, S., Buschow, C., Meinecke, P., Wolff, G., Gillessen-Kaesbach, G., Oldridge, M., Wilkie, A.O., Kömec, R., Mundlos, S. Am. J. Hum. Genet. (2000) [Pubmed]
  20. A Thai mother and son with distal symphalangism, hypoplastic carpal bones, microdontia, dental pulp stones, and narrowing of the zygomatic arch: a new distal symphalangism syndrome? Kantaputra, P.N., Kinoshita, A., Limwonges, C., Praditsup, O., Niikawa, N. Am. J. Med. Genet. (2002) [Pubmed]
  21. Excretion of MBDB and BDB in urine, saliva, and sweat following single oral administration. Kintz, P. Journal of analytical toxicology. (1997) [Pubmed]
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