Abstract
ROR2 is a member of the cell surface receptor tyrosine kinase (RTKs) family of proteins and is involved in the developmental morphogenesis of the skeletal, cardiovascular and genital systems. Mutations in ROR2 have been shown to cause two distinct human disorders, autosomal recessive Robinow syndrome and dominantly inherited Brachydactyly type B. The recessive form of Robinow syndrome is a disorder caused by loss-of-function mutations whereas Brachydactyly type B is a dominant disease and is presumably caused by gain-of-function mutations in the same gene. We have previously established that all the missense mutations causing Robinow syndrome in ROR2 are retained in the endoplasmic reticulum and therefore concluded that their loss of function is due to a defect in their intracellular trafficking. These mutations were in the distal portion of the frizzled-like cysteine rich domain and kringle domain. Here we report the identification of two novel mutations in the frizzled-like cysteine-rich domain of ROR2 causing Robinow syndrome. We establish the retention of the mutated proteins in the endoplasmic reticulum of HeLa cells and therefore failure to reach the plasma membrane. The clustering of Robinow-causing mutations in the extracellular frizzled-like cysteine-rich domain of ROR2 suggests a stringent requirement for the correct folding of this domain prior to export of ROR2 from the endoplasmic reticulum to the plasma membrane.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Afzal AR, Jeffery S (2003) One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B. Hum Mutat 22:1–11
Afzal AR, Rajab A, Fenske CD, Oldridge M, Elanko N, Ternes-Pereira E, Tuysuz B, Murday VA, Patton MA, Wilkie AOM, Jeffery S (2000) Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2. Nat Genet 25:419–422
Aridor M, Hannan LA (2000) Traffic Jam: a compendium of human diseases that affect intracellular transport processes. Traffic 1:836–851
Aridor M, Hannan LA (2002) Traffic Jam II: an update of diseases of intracellular transport. Traffic 3:781–790
Billiard J, Way DS, Seestaller-Wehr LM, Moran RA, Mangine A, Bodine PV (2005) The orphan receptor tyrosine kinase Ror2 modulates canonical Wnt signaling in osteoblastic cells. Mol Endocrinol 19:90–101
Chan SD, Karpf DB, Fowlkes ME, Hooks M, Bradley MS, Vuong V, Bambino T, Liu MY, Arnaud CD, Strewler GJ et al (1992) Two homologs of the Drosophila polarity gene frizzled (fz) are widely expressed in mammalian tissues. J Biol Chem 267:25202–25207
Chen Y, Bellamy WP, Seabra MC, Field MC, Ali BR (2005) ER-associated protein degradation is a common mechanism underpinning numerous monogenic diseases including Robinow syndrome. Hum Mol Genet 14:2559–2569
Dann CE, Hsieh JC, Rattner A, Sharma D, Nathans J, Leahy DJ (2001) Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 412:86–90
DeChiara TM, Kimble RB, Poueymirou WT, Rojas J, Masiakowski P, Valenzuela DM, Yancopoulos GD (2000) Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development. Nat Genet 24:271–274
Forrester WC (2002) The Ror receptor tyrosine kinase family. Cell Mol Life Sci 59:83–96
Huang H-C, Klein PS (2004) The Frizzled family: receptors for multiple signal transduction pathways. Genome Biol 5:234
Kameya S, Hawes NL, Chang B, Heckenlively JR, Naggert JK, Nishina PM (2002) Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6. Hum Mol Genet 11:1879–1886
Kaykas A, Yang-Snyder J, Heroux M, Shah KV, Bouvier M, Moon RT (2004) Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization. Nat Cell Biol 6:52–58
Matsuda T, Suzuki H, Oishi I, Kani S, Kuroda Y, Komori T, Sasaki A, Watanabe K, Minami Y (2003) The receptor tyrosine kinase Ror2 associates with the melanoma-associated antigen (MAGE) family protein Dlxin-1 and regulates its intracellular distribution. J Biol Chem 278:29057–29064
Masiakowski P, Yancopoulos GD (1998) The Wnt receptor CRD domain is also found in MuSK and related orphan receptor tyrosine kinases. Curr Biol 8:R407
McCracken AA, Brodsky JL (2003) Evolving questions and paradigm shifts in endoplasmic-reticulum-associated degradation (ERAD). Bioessays 25:868–877
Nomi M, Oishi I, Kani S, Suzuki H, Matsuda T, Yoda A, Kitamura M, Itoh K, Takeuchi S, Takeda K, Akira S, Ikeya M, Takada S, Minami Y (2001) Loss of mRor1 enhances the heart and skeletal abnormalities in mRor2-deficient mice: redundant and pleiotropic functions of mRor1 and mRor2 receptor tyrosine kinases. Mol Cell Biol 21:8329–8335
Oldridge M, Fortuna AM, Maringa M, Propping P, Mansour S, Pollitt C, DeChiara TM, Kimble RB, Valenzuela DM, Yancopoulos GD, Wilkie AOM (2000) Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B. Nat Genet 24:275–278
Patton MA, Afzal AR (2002) Robinow syndrome. J Med Genet 39:305–310
Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434:843–8450
Robinow M (1993) The Robinow (fetal face) syndrome: a continuing puzzle. Clin Dysmorphol 2:189–198
Robinow M, Silverman FN, Smith HD (1969) A newly recognized dwarfing syndrome. Am J Dis Child 117:645–651
Romisch K (2004) A cure for traffic jams: small molecule chaperones in the endoplasmic reticulum. Traffic 5:815–820
Roszmusz E, Patthy A, Trexler M, Patthy L (2001) Localization of disulfide bonds in the frizzled module of Ror1 receptor tyrosine kinase. J Biol Chem 276:18485–18490
Schwabe GC, Tinschert S, Buschow C, Meinecke P, Wolff G, Gillessen-Kaesbach G, Oldrige M, Wilkie AOM, Komec R, Mundlos S (2000) Distinct mutations in the receptor tyrosine kinase gene ROR2 cause bracydactyly type B. Am J Hum Genet 67:822–831
Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225
Schwabe GC, Trepczik B, Suring K, Brieske N, Tucker AS, Sharpe PT, Minami Y, Mundlos S (2004) Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome. Dev Dyn 229:400–410
Soliman AT, Rajab A, Alsalmi I, Bedair SMA (1998) Recessive Robinow syndrome: with emphasis on endocrine functions. Metabolism 47:1337–1343
Takeuchi S, Takeda K, Oishi I, Nomi M, Ikeya M, Itoh K, Tamura S, Ueda T, Hatta T, Otani H et al (2000) Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation. Genes Cells 5:71–78
Teebi AS (1990) Autosomal recessive Robinow syndrome. Am J Med Genet 35:64–68
Toomes C, Bottomley HM, Scott S, Mackey DA, Craig JE, Appukuttan B, Stout JT, Flaxel CJ, Zhang K, Black GC, Fryer A, Downey LM, Inglehearn CF (2004) Spectrum and frequency of FZD4 mutations in familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci 45:2083–2090
Tufan F, Cefle K, Turkmen S, Turkmen A, Zorba U, Dursun M, Ozturk S, Palanduz S, Ecder T, Mundlos S, Horn D (2005) Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome. Am J Med Genet A 136:185–189
van Bokhoven H, Celli J, Kayserili H, van Beusekom E, Balci S, Brussel W, Skovby F, Kerr B, Percin EF, Akarsu N, Brunner HG (2000) Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. Nat Genet 25:423–426
Wadia RS (1978) Recessively inherited costovertebral segmentation defect with mesomelia and peculiar facies (Covesdem syndrome), a new genetic entity? J Med Genet 15:123–127
Welch WJ (2004) Role of quality control pathways in human diseases involving protein misfolding. Semin Cell Dev Biol 15:31–38
Xu YK, Nusse R (1998) The Frizzled CRD domain is conserved in diverse proteins including several receptor tyrosine kinases. Curr Biol 8:R405–6
Yoda A, Oishi I, Minami Y (2003) Expression and function of the Ror-family receptor tyrosine kinases during development: lessons from genetic analyses of nematodes, mice, and humans. J Recept Signal Transduct Res 23:1–15
Acknowledgments
We are grateful to Prof. Y. Minami and Department of Biomedical Regulation, Kobe University School of Medicine, Kobe, Japan for providing the mouse pcDNA3-Ror2WT-HA plasmid. Thanks to Vanda Lopes for assistance and Prof. Miguel Seabra (supported by the Wellcome Trust) for reagents and facilities. ARA was supported by the Wellcome Trust.
Author information
Authors and Affiliations
Corresponding author
Additional information
GenBank accession number ROR2, M97639.
Rights and permissions
About this article
Cite this article
Ali, B.R., Jeffery, S., Patel, N. et al. Novel Robinow syndrome causing mutations in the proximal region of the frizzled-like domain of ROR2 are retained in the endoplasmic reticulum. Hum Genet 122, 389–395 (2007). https://doi.org/10.1007/s00439-007-0409-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-007-0409-0