Dr. Esther de Graaff
Cell Biology, Faculty of Science, Utrecht University
Padualaan 8, 3584 CH Utrecht
Esther de Graaff studied biomedical sciences in Leiden, which was followed by a PhD at the department of Clinical Genetics at the Erasmus MC, Rotterdam, where she studied the mechanism of trinucleotide amplification in the Fragile X syndrome. After her graduation in 1996, she started her training in molecular neurodevelopment at the National Institute of Medical Research, London, UK. She there focussed on the role of different isoforms of RET in the development of the kidney and enteric nervous system. Her work lead to the identification of a cooperative and balanced interaction between the G protein-coupled receptor EDNRB and the receptor tyrosine kinase RET signaling pathways. Disturbance in this interaction leads to Hirschsprung’s disease, an (enteric) neuronal migration defect. In 2001 she returned to Rotterdam and started her own research group at the Department of Clinical Genetics. There she identified a long range, cis-acting element of SHH, a molecule essential for the patterning of the anterior-posterior (thumb-little finger) axis of the limb. The mechanism by which this element, at a remarkable distance of 1 Mb from SHH, regulated its expression in the limb only was studied with a Vernieuwingsimpuls VIDI award from ZonMW.
In 2009 she moved to the Department of Neuroscience, where she started her work on identification of antigens for neuronal auto-immune antibodies, attacking the central nervous system. Since april 2011 she is assistant professor at the Department of Cell Biology at Utrecht University.
A pdf of a short CV can be downloaded here.
Recently she was inteviewed at the FENS meeting in Barcelona (July 2012) for “The naked Scientist”:
In general our group is interested in getting a better understanding of how the brain both develops and functions. Neurodevelopment encompasses many different processes, such as neurogenesis, migration and differentiation. Precursors of neurons are generally formed in one position in the brain, but have to migrate to their right location. This requires many components, such as extracellular matrix proteins, guiding the neuron in the proper directions but also intracellular proteins, such as a fully functional microtubule network with its interacting proteins. We mainly study migration defects that are caused by defective motor proteins or their adaptors.
The differentiation of the neuron is mainly studied with an emphasis on the emergence of the dendrites and axon: what determines where the axon is formed and which proteins are involved in maintaining the neuron’s polarity.
In another line of research we study anomalies of the brain in adults (in close collaboration with Prof. Dr. Sillevis-Smitt from the department of Neurology, Erasmus MC, Rotterdam). More specifically we are interested in an anomaly that is characterized by sub acute onset of short-term memory loss, psychiatric symptoms, confusion and seizures and can be caused by an autoimmune inflammation of the brain. So far autoimmune antibodies targeting a variety of different intracellular or extracellular proteins have been identified. Antibodies against several known synaptic receptors have been described, such as the excitatory glutamate NMDA receptors, the AMPA receptors and the inhibitory GABAB receptors. However, in a large number of patients, with antibodies recognizing neuronal proteins (see figure) the epitope is unknown.
A second goal of our lab therefore is the identification of these proteins. Besides identifying these proteins, we also aim to get a better understanding of both the disease mechanism and the effect of the antibodies on neuronal functioning.
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Probst C, Komorowski L, de Graaff E, van Coevorden-Hameete M, Rogemond V, Honnorat J, Sabeter L, Graus F, Jarius S, Voltz R, Wildemann B, Franciotta D, Blöcker IM, Schlumberger W, Stöcker W, Sillevis Smitt PA. Standardized test for anti-Tr/DNER in patients with paraneoplastic cerebellar degeneration. Neurol Neuroimmunol Neuroinflamm. 2015 Feb 26;2(2):e68. doi: 10.1212/NXI.0000000000000068. eCollection 2015 Apr. PubMed PMID: 25745634; PubMed Central PMCID: PMC4345632.
Hessel EV, de Wit M, Wolterink-Donselaar IG, Karst H, de Graaff E, van Lith HA, de Bruijn E, de Sonnaville S, Verbeek NE, Lindhout D, de Kovel CG, Koeleman BP, van Kempen M, Brilstra E, Cuppen E, Loos M, Spijker SS, Kan AA, Baars SE, van Rijen PC, Gosselaar PH, Groot Koerkamp MJ, Holstege FC, van Duijn C, Vergeer J, Moll HA, Taubøll E, Heuser K, Ramakers GM, Pasterkamp RJ, van Nieuwenhuizen O, Hoogenraad CC, Kas MJ, de Graan PN. Identification of Srp9 as a febrile seizure susceptibility gene. Ann Clin Transl Neurol. 2014 Apr;1(4):239-50. doi: 10.1002/acn3.48. Epub 2014 Mar 12. PubMed PMID: 25590037; PubMed Central PMCID: PMC4292741.
Jaarsma D, van den Berg R, Wulf PS, van Erp S, Keijzer N, Schlager MA, de Graaff E, De Zeeuw CI, Pasterkamp RJ, Akhmanova A, Hoogenraad CC. A role for Bicaudal-D2 in radial cerebellar granule cell migration. Nat Commun. 2014 Mar 11;5:3411. doi: 10.1038/ncomms4411. PubMed PMID: 24614806.
van Coevorden-Hameete MH, de Graaff E, Titulaer MJ, Hoogenraad CC, Sillevis Smitt PA. Molecular and cellular mechanisms underlying anti-neuronal antibody mediated disorders of the central nervous system. Autoimmun Rev. 2014 Mar;13(3):299-312. doi: 10.1016/j.autrev.2013.10.016. Epub 2013 Nov 10. Review. PubMed PMID: 24225076.
Spangler SA, Schmitz SK, Kevenaar JT, de Graaff E, de Wit H, Demmers J, Toonen RF, and Hoogenraad CC. Liprin-alpha2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission. J Cell Biol. 2013 Jun 10, 201(6): 915-28. PMID: 23751498
De Graaff E, Maat P, Hulsenboom E, van den Berg R, Demmer J, Lugtenburg PJ, Hoogenraad CC, Sillevis Smitt P (2012) “Identification of delta/notch-like epidermal growth factor-related receptor as the Tr antigen in paraneoplastic cerebellar degeneration.” Ann Neurol 71(6):815-24.
Zhao T, De Graaff E, Breedveld GJ, Loda A, Severijnen LA, Wouters CH, Verheijen FW, Dekker MC, Montagna P, Willemsen R, Oostra BA and Bonifati V (2011) Loss of Nuclear Activity of the FBXO7 Protein in Patients with Parkinsonian-Pyramidal Syndrome (PARK15). PLoS One. 6(2):e16983. PMID: 21347293
Poulton CJ, Schot R, Kia SK, Jones M, Verheijen FW, Venselaar H, de Wit MC, de Graaff E, Bertoli-Avella AM, Mancini, GM (2011) “Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors.” Am J Hum Genet 89(2): 265-76.
Spangler SA, Jaarsma D, de Graaff E, Wulf, PS, Akhmanova A, Hoogenraad CC (2011) “Differential expression of liprin-alpha family proteins in the brain suggests functional diversification.” J Comp Neurol 519(15):3040-60.
Schlager, M. A., L. C. Kapitein, I. Grigoriev, G. M. Burzynski, P. S. Wulf, N. Keijzer, et al. (2010). “Pericentrosomal targeting of Rab6 secretory vesicles by Bicaudal-D-related protein 1 (BICDR-1) regulates neuritogenesis.” EMBO J 29(10): 1637-51. PMID: 20360680
Alves, M. M., G. Burzynski, J. M. Delalande, J. Osinga, A. van der Goot, A. M. Dolga, et al. (2010). “KBP interacts with SCG10, linking Goldberg-Shprintzen syndrome to microtubule dynamics and neuronal differentiation.” Hum Mol Genet 19(18): 3642-3651. PMID: 20621975
Lodder, E. M., B. H. Eussen, D. A. van Hassel, A. J. Hoogeboom, P. J. Poddighe, J. H. Coert, et al. (2009). “Implication of long-distance regulation of the HOXA cluster in a patient with postaxial polydactyly.” Chromosome Res 17(6): 737-44. PMID: 19672683
Di Fonzo, A., M. C. Dekker, P. Montagna, A. Baruzzi, E. H. Yonova, L. Correia Guedes, et al. (2009). “FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome.” Neurology 72(3): 240-5. PMID: 19038853
Verkerk, A. J., R. Schot, B. Dumee, K. Schellekens, S. Swagemakers, A. M. Bertoli-Avella, et al. (2009). “Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy.” Am J Hum Genet 85(1): 40-52. PMID: 19559397
Lodder, E. M., A. J. Hoogeboom, J. H. Coert and E. de Graaff (2008). “Deletion of 1 amino acid in Indian hedgehog leads to brachydactylyA1.” Am J Med Genet A 146A(16): 2152-4. PMID: 18629882
Wong, A., S. Bogni, P. Kotka, E. de Graaff, V. D’Agati, F. Costantini, et al. (2005). “Phosphotyrosine 1062 is critical for the in vivo activity of the Ret9 receptor tyrosine kinase isoform.” Mol Cell Biol 25(21): 9661-73.
Brooks, A. S., A. M. Bertoli-Avella, G. M. Burzynski, G. J. Breedveld, J. Osinga, L. G. Boven, et al. (2005). “Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems.” Am J Hum Genet 77(1): 120-6.
Barlow, A., E. de Graaff and V. Pachnis (2003). “Enteric nervous system progenitors are coordinately controlled by the G protein-coupled receptor EDNRB and the receptor tyrosine kinase RET.” Neuron 40(5): 905-16.
Galjaard, R. J., A. P. Smits, J. H. Tuerlings, A. G. Bais, A. M. Bertoli Avella, G. Breedveld, et al. (2003). “A new locus for postaxial polydactyly type A/B on chromosome 7q21-q34.” Eur J Hum Genet 11(5): 409-15.
Galjaard, R. J., H. C. van der Linde, B. H. Eussen, B. B. de Vries, C. H. Wouters, B. A. Oostra, et al. (2003). “Isolated postaxial polydactyly type B with mosaicism of a submicroscopic unbalanced translocation leading to an extended phenotype in offspring.” Am J Med Genet A 121A(2): 168-73.
Lettice, L. A., S. J. Heaney, L. A. Purdie, L. Li, P. de Beer, B. A. Oostra, et al. (2003). “A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly.” Hum Mol Genet 12(14): 1725-35.
Natarajan, D., C. Marcos-Gutierrez, V. Pachnis and E. de Graaff (2002). “Requirement of signalling by receptor tyrosine kinase RET for the directed migration of enteric nervous system progenitor cells during mammalian embryogenesis.” Development 129(22): 5151-60.
van Baren, M. J., H. C. van der Linde, G. J. Breedveld, W. M. Baarends, P. Rizzu, E. de Graaff, et al. (2002). “A double RING-H2 domain in RNF32, a gene expressed during sperm formation.” Biochem Biophys Res Commun 292(1): 58-65.
de Graaff, E., S. Srinivas, C. Kilkenny, V. D’Agati, B. S. Mankoo, F. Costantini, et al. (2001). “Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis.” Genes Dev 15(18): 2433-44.
Hutton, M., C. L. Lendon, P. Rizzu, M. Baker, S. Froelich, H. Houlden, et al. (1998). “Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17.” Nature 393(6686): 702-5.
Bontekoe, C. J., E. de Graaff, I. M. Nieuwenhuizen, R. Willemsen and B. A. Oostra (1997). “FMR1 premutation allele (CGG)81 is stable in mice.” Eur J Hum Genet 5(5): 293-8.
Schwemmle, S., E. de Graaff, H. Deissler, D. Glaser, D. Wohrle, I. Kennerknecht, et al. (1997). “Characterization of FMR1 promoter elements by in vivo-footprinting analysis.” Am J Hum Genet 60(6): 1354-62.
Malter, H. E., J. C. Iber, R. Willemsen, E. de Graaff, J. C. Tarleton, J. Leisti, et al. (1997). “Characterization of the full fragile X syndrome mutation in fetal gametes.” Nat Genet 15(2): 165-9.
de Graaff, E., B. B. de Vries, R. Willemsen, J. O. van Hemel, S. Mohkamsing, B. A. Oostra, et al. (1996). “The fragile X phenotype in a mosaic male with a deletion showing expression of the FMR1 protein in 28% of the cells.” Am J Med Genet 64(2): 302-8.
Verheij, C., E. de Graaff, C. E. Bakker, R. Willemsen, P. J. Willems, N. Meijer, et al. (1995). “Characterization of FMR1 proteins isolated from different tissues.” Hum Mol Genet 4(5): 895-901.
de Graaff, E., R. Willemsen, N. Zhong, C. E. de Die-Smulders, W. T. Brown, G. Freling, et al. (1995). “Instability of the CGG repeat and expression of the FMR1 protein in a male fragile X patient with a lung tumor.” Am J Hum Genet 57(3): 609-18.
de Graaff, E., P. Rouillard, P. J. Willems, A. P. Smits, F. Rousseau and B. A. Oostra (1995). “Hotspot for deletions in the CGG repeat region of FMR1 in fragile X patients.” Hum Mol Genet 4(1): 45-9.
van den Ouweland, A. M., B. B. de Vries, P. L. Bakker, W. H. Deelen, E. de Graaff, J. O. van Hemel, et al. (1994). “DNA diagnosis of the fragile X syndrome in a series of 236 mentally retarded subjects and evidence for a reversal of mutation in the FMR-1 gene.” Am J Med Genet 51(4): 482-5.
Chiurazzi, P., E. de Graaff, J. Ng, A. J. Verkerk, S. Wolfson, G. S. Fisch, et al. (1994). “No apparent involvement of the FMR1 gene in five patients with phenotypic manifestations of the fragile X syndrome.” Am J Med Genet 51(4): 309-14.
Hamel, B. C., A. P. Smits, E. de Graaff, D. F. Smeets, F. Schoute, B. H. Eussen, et al. (1994). “Segregation of FRAXE in a large family: clinical, psychometric, cytogenetic, and molecular data.” Am J Hum Genet 55(5): 923-31.
Hermans, M. M., E. De Graaff, M. A. Kroos, S. Mohkamsing, B. J. Eussen, M. Joosse, et al. (1994). “The effect of a single base pair deletion (delta T525) and a C1634T missense mutation (pro545leu) on the expression of lysosomal alpha-glucosidase in patients with glycogen storage disease type II.” Hum Mol Genet 3(12): 2213-8.
Meijer, H., E. de Graaff, D. M. Merckx, R. J. Jongbloed, C. E. de Die-Smulders, J. J. Engelen, et al. (1994). “A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome.” Hum Mol Genet 3(4): 615-20.
Reyniers, E., L. Vits, K. De Boulle, B. Van Roy, D. Van Velzen, E. de Graaff, et al. (1993). “The full mutation in the FMR-1 gene of male fragile X patients is absent in their sperm.” Nat Genet 4(2): 143-6.
De Boulle, K., A. J. Verkerk, E. Reyniers, L. Vits, J. Hendrickx, B. Van Roy, et al. (1993). “A point mutation in the FMR-1 gene associated with fragile X mental retardation.” Nat Genet 3(1): 31-5.
Bontekoe, C. J., E. de Graaff, G. J. Breedveld, B. A. Oostra and P. Heutink (1993). “Dinucleotide repeat polymorphism at D11S994 locus.” Hum Mol Genet 2(10): 1747.
Verheij, C., C. E. Bakker, E. de Graaff, J. Keulemans, R. Willemsen, A. J. Verkerk, et al. (1993). “Characterization and localization of the FMR-1 gene product associated with fragile X syndrome.” Nature 363(6431): 722-4.
de Vries, B. B., A. M. Wiegers, E. de Graaff, A. J. Verkerk, J. O. Van Hemel, D. J. Halley, et al. (1993). “Mental status and fragile X expression in relation to FMR-1 gene mutation.” Eur J Hum Genet 1(1): 72-9.
Verkerk, A. J., E. de Graaff, K. De Boulle, E. E. Eichler, D. S. Konecki, E. Reyniers, et al. (1993). “Alternative splicing in the fragile X gene FMR1.” Hum Mol Genet 2(4): 399-404.
Hermans, M. M., E. de Graaff, M. A. Kroos, H. A. Wisselaar, R. Willemsen, B. A. Oostra, et al. (1993). “The conservative substitution Asp-645–>Glu in lysosomal alpha-glucosidase affects transport and phosphorylation of the enzyme in an adult patient with glycogen-storage disease type II.” Biochem J 289 ( Pt 3): 687-93.
Hermans, M. M., M. A. Kroos, E. de Graaff, B. A. Oostra and A. J. Reuser (1993). “Two mutations affecting the transport and maturation of lysosomal alpha-glucosidase in an adult case of glycogen storage disease type II.” Hum Mutat 2(4): 268-73.
van Kamp, H., W. E. Fibbe, R. P. Jansen, M. van der Keur, E. de Graaff, R. Willemze, et al. (1992). “Clonal involvement of granulocytes and monocytes, but not of T and B lymphocytes and natural killer cells in patients with myelodysplasia: analysis by X-linked restriction fragment length polymorphisms and polymerase chain reaction of the phosphoglycerate kinase gene.” Blood 80(7): 1774-80.
Kal, H. B., E. de Graaff, A. H. Van Berkel and H. H. Goedoen (1992). “Responses of experimental rat tumours and a mouse colon tumour to flavone acetic acid.” In Vivo 6(1): 73-5.
Hermans, M. M., E. de Graaff, M. A. Kroos, H. A. Wisselaar, B. A. Oostra and A. J. Reuser (1991). “Identification of a point mutation in the human lysosomal alpha-glucosidase gene causing infantile glycogenosis type II.” Biochem Biophys Res Commun 179(2): 919-26.
van Coevorden-Hameete MH, de Graaff E, Titulaer MJ, Hoogenraad CC, and Sillevis Smitt PA. Molecular and cellular mechanisms underlying anti-neuronal antibody mediated disorders of the central nervous system. Autoimmun Rev. 2013 Nov 10 PMID: 24225076.
de Graaff, E. and S. H. Kozin (2009). “Genetics of radial deficiencies.” J Bone Joint Surg Am 91 Suppl 4: 81-6.
de Graaff, E., van Baaren, M. J. and Heutink, P. (2002) “Clinical genetics of the upper Limb”. In : The Pediatric Upper Limb. Martin Dunitz Ltd, Eds. Hovius, S.E.R., Foucher, G. and Raimondi, P.L.: 9-20.