ZFIN ID: ZDB-LAB-140819-1
Functional genomics and therapeutics / ENT
PI/Director: Kremer, Hannie
Co-PI / Senior
van Wijk, Erwin
Contact Person:
Email: erwin.vanwyk@radboudumc.nl
Address: Genome Research Radboud University Medical Centre Nijmegen, Netherlands
Country: Netherlands
Phone: +31 24 3618847
Line Designation: rmc

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Usher Syndrome: Genetics, Functional Genomics and Therapeutics

Usher syndrome is genetically and clinically heterogeneous. The syndrome combines hearing impairment, retinitis pigmentosa and in part of the patients vestibular impairment. Usher syndrome type IIa (USH2a), the most common type, is caused by mutations in the USH2A gene. Other genes involved in Usher syndrome are MYO7A, USH1C, CDH23, PCDH15 and USH1G (type I), GPR98 and DFNB31 (type II) and USH3A (type III). Also, defects in the USH2A gene are an important cause of non-syndromic retinitis pigmentosa. Usher proteins co-function in a protein network which explains why defects in genes encoding functionally different proteins are causative for one and the same disorder. We have a specific interest in the USH2A protein and whirlin. Recently, we have shown that NINL, which we identified as an interaction partner of USH2A, connects proteins involved in different retinal degeneration disorders (Usher syndrome, Leber congenital amaurosis and Bardet Biedl syndrome). This suggests an overlap in the molecular pathogenesis of these disorders. Further unravelling of the USH protein network is ongoing by using yeast two-hybrid screening and tandem affinity purification (TAP). The mechanisms of hearing impairment in Usher syndrome are at least partly understood. Those of retinal degeneration in Usher syndrome are largely unknown but the localization of the Usher proteins in the region of the connecting cilium of photoreceptor cells suggests that dysfunction of this structure which heavily functions in transport, is involved. To further study the function of Usher proteins and the mechanisms of retinal degeneration we are introducing zebrafish as a model organism. In this model we shall address therapeutic strategies for USH2A-associated retinal degeneration.

To facilitate DNA diagnostics an Usher mutation chip has been developed in collaboration with Asper Biotech. With the chip all known mutations in all Usher genes identified so far, can be detected. The chip is being updated every 2-3 years and is available for DNA diagnostics via Asper Biotech. The research is a close collaboration between the ENT Department and the Genetics Department.

de Vrieze, Erik Post-Doc Peter, Theo Post-Doc Dona, Margo Graduate Student
Slijkerman, Ralph Graduate Student Hetterschijt, Lisette Research Staff

Schellens, R.T.W., Slijkerman, R.W.N., Hetterschijt, L., Peters, T., Broekman, S., Clemént, A., Westerfield, M., Phillips, J.B., Boldt, K., Kremer, H., De Vrieze, E., Van Wijk, E. (2022) Affinity purification of in vivo assembled whirlin-associated protein complexes from the zebrafish retina. Journal of proteomics. 266:104666
Reurink, J., de Vrieze, E., Li, C.H.Z., van Berkel, E., Broekman, S., Aben, M., Peters, T., Oostrik, J., Neveling, K., Venselaar, H., Ramos, M.G., Gilissen, C., Astuti, G.D.N., Galbany, J.C., van Lith-Verhoeven, J.J.C., Ockeloen, C.W., Haer-Wigman, L., Hoyng, C.B., Cremers, F.P.M., Kremer, H., Roosing, S., van Wijk, E. (2022) Scrutinizing pathogenicity of the USH2A c.2276 G > T; p.(Cys759Phe) variant. NPJ genomic medicine. 7:37
Moran, A.L., Carter, S.P., Kaylor, J.J., Jiang, Z., Broekman, S., Dillon, E.T., Gómez Sánchez, A., Minhas, S.K., van Wijk, E., Radu, R.A., Travis, G.H., Carey, M., Blacque, O.E., Kennedy, B.N. (2022) Dawn and dusk peaks of outer segment phagocytosis, and visual cycle function require Rab28. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 36:e22309
Kamel, S.M., Broekman, S., Tessadori, F., van Wijk, E., Bakkers, J. (2022) The zebrafish cohesin protein Sgo1 is required for cardiac function and eye development. Developmental dynamics : an official publication of the American Association of Anatomists. 251(8):1357-1367
Dona, M., Lamers, M., Rohde, S., Gorissen, M., Timmers, H.J.L.M. (2021) Targeting the Redox Balance Pathway Using Ascorbic Acid in sdhb Zebrafish Mutant Larvae. Cancers. 13(20):
de Vrieze, E., de Bruijn, S.E., Reurink, J., Broekman, S., van de Riet, V., Aben, M., Kremer, H., van Wijk, E. (2021) Efficient Generation of Knock-In Zebrafish Models for Inherited Disorders Using CRISPR-Cas9 Ribonucleoprotein Complexes. International Journal of Molecular Sciences. 22(17):
Schellens, R., de Vrieze, E., Graave, P., Broekman, S., Nagel-Wolfrum, K., Peters, T., Kremer, H., Collin, R.W.J., van Wijk, E. (2021) Zebrafish as a Model to Evaluate a CRISPR/Cas9-Based Exon Excision Approach as a Future Treatment Option for EYS-Associated Retinitis Pigmentosa. International Journal of Molecular Sciences. 22(17):
Engelke, U.F., van Outersterp, R.E., Merx, J., van Geenen, F.A., van Rooij, A., Berden, G., Huigen, M.C., Kluijtmans, L.A., Peters, T.M., Al-Shekaili, H.H., Leavitt, B.R., de Vrieze, E., Broekman, S., van Wijk, E., Tseng, L.A., Kulkarni, P., Rutjes, F.P., Mecinovic, J., Struys, E.A., Jansen, L.A., Gospe, S.M., Mercimek-Andrews, S., Hyland, K., Willemsen, M.A., Bok, L.A., Van Karnebeek, C.D., Wevers, R.A., Boltje, T.J., Oomens, J., Martens, J., Coene, K.L. (2021) Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy. The Journal of Clinical Investigation. 131(15):
Quint, W.H., Tadema, K.C.D., de Vrieze, E., Lukowicz, R.M., Broekman, S., Winkelman, B.H.J., Hoevenaars, M., de Gruiter, H.M., van Wijk, E., Schaeffel, F., Meester-Smoor, M., Miller, A.C., Willemsen, R., Klaver, C.C.W., Iglesias, A.I. (2021) Loss of Gap Junction Delta-2 (GJD2) gene orthologs leads to refractive error in zebrafish. Communications biology. 4:676
Bassani, S., Beelen, E., Rossel, M., Voisin, N., Morgan, A., Arribat, Y., Chatron, N., Chrast, J., Cocca, M., Delprat, B., Faletra, F., Giannuzzi, G., Guex, N., Machavoine, R., Pradervand, S., Smits, J.J., van de Kamp, J.M., Ziegler, A., Amati, F., Marlin, S., Kremer, H., Locher, H., Maurice, T., Gasparini, P., Girotto, G., Reymond, A. (2021) Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss. Human molecular genetics. 30(19):1785-1796
Dulla, K., Slijkerman, R., van Diepen, H.C., Albert, S., Dona, M., Beumer, W., Turunen, J.J., Chan, H.L., Schulkens, I.A., Vorthoren, L., Besten, C.D., Buil, L., Schmidt, I., Miao, J., Venselaar, H., Zang, J., Neuhauss, S.C.F., Peters, T., Broekman, S., Pennings, R., Kremer, H., Platenburg, G., Adamson, P., de Vrieze, E., van Wijk, E. (2021) Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations. Molecular therapy : the journal of the American Society of Gene Therapy. 29(8):2441-2455
Karjosukarso, D.W., Ali, Z., Peters, T.A., Zhang, J.Q.C., Hoogendoorn, A.D.M., Garanto, A., van Wijk, E., Jensen, L.D., Collin, R.W.J. (2020) Modeling ZNF408-Associated FEVR in Zebrafish Results in Abnormal Retinal Vasculature. Investigative ophthalmology & visual science. 61:39
Toms, M., Dubis, A.M., de Vrieze, E., Tracey-White, D., Mitsios, A., Hayes, M., Broekman, S., Baxendale, S., Utoomprurkporn, N., Bamiou, D., Bitner-Glindzicz, M., Webster, A.R., Van Wijk, E., Moosajee, M. (2020) Clinical and preclinical therapeutic outcome metrics for USH2A-related disease. Human molecular genetics. 29(11):1882-1899
van Dam, T.J.P., Kennedy, J., van der Lee, R., de Vrieze, E., Wunderlich, K.A., Rix, S., Dougherty, G.W., Lambacher, N.J., Li, C., Jensen, V.L., Leroux, M.R., Hjeij, R., Horn, N., Texier, Y., Wissinger, Y., van Reeuwijk, J., Wheway, G., Knapp, B., Scheel, J.F., Franco, B., Mans, D.A., van Wijk, E., Képès, F., Slaats, G.G., Toedt, G., Kremer, H., Omran, H., Szymanska, K., Koutroumpas, K., Ueffing, M., Nguyen, T.T., Letteboer, S.J.F., Oud, M.M., van Beersum, S.E.C., Schmidts, M., Beales, P.L., Lu, Q., Giles, R.H., Szklarczyk, R., Russell, R.B., Gibson, T.J., Johnson, C.A., Blacque, O.E., Wolfrum, U., Boldt, K., Roepman, R., Hernandez-Hernandez, V., Huynen, M.A. (2019) CiliaCarta: An integrated and validated compendium of ciliary genes. PLoS One. 14:e0216705
Arjona, F.J., Latta, F., Mohammed, S.G., Thomassen, M., van Wijk, E., Bindels, R.J.M., Hoenderop, J.G.J., de Baaij, J.H.F. (2018) SLC41A1 is essential for magnesium homeostasis in vivo. Pflugers Archiv : European journal of physiology. 471(6):845-860
Slijkerman, R., Goloborodko, A., Broekman, S., de Vrieze, E., Hetterschijt, L., Peters, T., Gerits, M., Kremer, H., van Wijk, E. (2018) Poor Splice-Site Recognition in a Humanized Zebrafish Knockin Model for the Recurrent Deep-Intronic c.7595-2144A>G Mutation in USH2A. Zebrafish. 15(6):597-609
Messchaert, M., Dona, M., Broekman, S., Peters, T.A., Corral-Serrano, J.C., Slijkerman, R.W.N., van Wijk, E., Collin, R.W.J. (2018) Eyes shut homolog is important for the maintenance of photoreceptor morphology and visual function in zebrafish. PLoS One. 13:e0200789
Corral-Serrano, J.C., Messchaert, M., Dona, M., Peters, T.A., Kamminga, L.M., van Wijk, E., Collin, R.W.J. (2018) C2orf71a/pcare1 is important for photoreceptor outer segment morphogenesis and visual function in zebrafish. Scientific Reports. 8:9675
Dona, M., Slijkerman, R., Lerner, K., Broekman, S., Wegner, J., Howat, T., Peters, T., Hetterschijt, L., Boon, N., de Vrieze, E., Sorusch, N., Wolfrum, U., Kremer, H., Neuhauss, S., Zang, J., Kamermans, M., Westerfield, M., Phillips, J., van Wijk, E. (2018) Usherin defects lead to early-onset retinal dysfunction in zebrafish. Experimental Eye Research. 173:148-159
Weisz Hubshman, M., Broekman, S., van Wijk, E., Cremers, F., Abu-Diab, A., Samer, K., Tzur, S., Lagovsky, I., Smirin-Yosef, P., Sharon, D., Haer-Wigman, L., Banin, E., Basel-Vanagaite, L., de Vrieze, E. (2017) Whole-exome sequencing reveals POC5 as a novel gene associated with autosomal recessive retinitis pigmentosa. Human molecular genetics. 27(4):614-624
Samarut, É., Dona, M., Yoganantharjah, P. (2017) Zebrafish Ride the Danube's Wave for the 10th European Zebrafish Meeting. Zebrafish. 15(1):79-83
Roosing, S., Rosti, R.O., Rosti, B., de Vrieze, E., Silhavy, J.L., van Wijk, E., Wakeling, E., Gleeson, J.G. (2016) Identification of a homozygous nonsense mutation in KIAA0556 in a consanguineous family displaying Joubert syndrome. Human genetics. 135(8):919-21
Bachmann-Gagescu, R., Dona, M., Hetterschijt, L., Tonnaer, E., Peters, T., de Vrieze, E., Mans, D.A., van Beersum, S.E., Phelps, I.G., Arts, H.H., Keunen, J.E., Ueffing, M., Roepman, R., Boldt, K., Doherty, D., Moens, C.B., Neuhauss, S.C., Kremer, H., van Wijk, E. (2015) The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3-Regulated Vesicle Trafficking. PLoS Genetics. 11:e1005575
Dona, M., Bachmann-Gagescu, R., Texier, Y., Toedt, G., Hetterschijt, L., Tonnaer, E.L., Peters, T.A., van Beersum, S.E., Bergboer, J.G., Horn, N., de Vrieze, E., Slijkerman, R.W., van Reeuwijk, J., Flik, G., Keunen, J.E., Ueffing, M., Gibson, T.J., Roepman, R., Boldt, K., Kremer, H., van Wijk, E. (2015) NINL and DZANK1 Co-function in Vesicle Transport and Are Essential for Photoreceptor Development in Zebrafish. PLoS Genetics. 11:e1005574
Slijkerman, R.W., Song, F., Astuti, G.D., Huynen, M.A., van Wijk, E., Stieger, K., Collin, R.W. (2015) The pros and cons of vertebrate animal models for functional and therapeutic research on inherited retinal dystrophies. Progress in Retinal and Eye Research. 48:137-59
de Vrieze, E., Zethof, J., Schulte-Merker, S., Flik, G., Metz, J.R. (2015) Identification of novel osteogenic compounds by an ex-vivo Sp7:luciferase zebrafish scale assay. Bone. 74:106-13
Roosing, S., Lamers, I.J., de Vrieze, E., van den Born, L.I., Lambertus, S., Arts, H.H., POC1B Study Group, Peters, T.A., Hoyng, C.B., Kremer, H., Hetterschijt, L., Letteboer, S.J., van Wijk, E., Roepman, R., den Hollander, A.I., Cremers, F.P. (2014) Disruption of the Basal Body Protein POC1B Results in Autosomal-Recessive Cone-Rod Dystrophy. American journal of human genetics. 95(2):131-142
de Vrieze, E., van de Wiel, S.M., Zethof, J., Flik, G., Klaren, P.H., Arjona, F.J. (2014) Knockdown of monocarboxylate transporter 8 (mct8) disturbs brain development and locomotion in zebrafish. Endocrinology. 155(6):2320-30
de Vrieze, E., Moren, M., Metz, J.R., Flik, G., Lie, K.K. (2014) Arachidonic acid enhances turnover of the dermal skeleton: studies on zebrafish scales. PLoS One. 9:e89347
de Vrieze, E., van Kessel, M.A., Peters, H.M., Spanings, F.A., Flik, G., and Metz, J.R. (2014) Prednisolone induces osteoporosis-like phenotype in regenerating zebrafish scales. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 25(2):567-78
van Wijk, X.M., Thijssen, V.L., Lawrence, R., van den Broek, S.A., Dona, M., Naidu, N., Oosterhof, A., van de Westerlo, E.M., Kusters, L.J., Khaled, Y., Jokela, T.A., Nowak-Sliwinska, P., Kremer, H., Stringer, S.E., Griffioen, A.W., van Wijk, E., van Delft, F.L., and van Kuppevelt, T.H. (2013) Interfering with UDP-GlcNAc metabolism and heparan sulfate expression using a sugar analog reduces angiogenesis. ACS Chemical Biology. 8(10):2331-8
Collin, R.W., Nikopoulos, K., Dona, M., Gilissen, C., Hoischen, A., Boonstra, F.N., Poulter, J.A., Kondo, H., Berger, W., Toomes, C., Tahira, T., Mohn, L.R., Blokland, E.A., Hetterschijt, L., Ali, M., Groothuismink, J.M., Duijkers, L., Inglehearn, C.F., Sollfrank, L., Strom, T.M., Uchio, E., van Nouhuys, C.E., Kremer, H., Veltman, J.A., van Wijk, E., and Cremers, F.P. (2013) ZNF408 is mutated in familial exudative vitreoretinopathy and is crucial for the development of zebrafish retinal vasculature. Proceedings of the National Academy of Sciences of the United States of America. 110(24):9856-9861
Wunderink, Y.S., de Vrieze, E., Metz, J.R., Halm, S., Martínez-Rodríguez, G., Flik, G., Klaren, P.H., and Mancera, J.M. (2012) Subfunctionalization of POMC paralogues in Senegalese sole (Solea senegalensis). General and comparative endocrinology. 175(3):407-415
Arjona, F.J., de Vrieze, E., Visser, T.J., Flik, G., and Klaren, P.H. (2011) Identification and Functional Characterization of Zebrafish Solute Carrier Slc16a2 (Mct8) as a Thyroid Hormone Membrane Transporter. Endocrinology. 152(12):5065-73
de Vrieze, E., Sharif, F., Metz, J.R., Flik, G., and Richardson, M.K. (2011) Matrix metalloproteinases in osteoclasts of ontogenetic and regenerating zebrafish scales. Bone. 48(4):704-712
Naranjo, S., Voesenek, K., de la Calle-Mustienes, E., Robert-Moreno, A., Kokotas, H., Grigoriadou, M., Economides, J., Van Camp, G., Hilgert, N., Moreno, F., Alsina, B., Petersen, M.B., Kremer, H., and Gómez-Skarmeta, J.L. (2010) Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing. Human genetics. 128(4):411-419
Gosens, I., van Wijk, E., Kersten, F.F., Krieger, E., van der Zwaag, B., Märker, T., Letteboer, S.J., Dusseljee, S., Peters, T., Spierenburg, H.A., Punte, I.M., Wolfrum, U., Cremers, F.P., Kremer, H., and Roepman, R. (2007) MPP1 links the Usher protein network and the Crumbs protein complex in the retina. Human molecular genetics. 16(16):1993-2003