Key publications
All Publications
- Ratbi Ilham, Falkenberg Kim D., Sommen Manou, Al-Sheqaih Nada, Guaoua Soukaina, Vandeweyer Geert, Urquhart Jill E., Chandler Kate E., Williams Simon G., Roberts Neil A., El Alloussi Mustapha, Black Graeme C., Ferdinandusse Sacha, Ramdi Hind, Heimler Audrey, Fryer Alan, Lynch Sally-Ann, Cooper Nicola, Ong Kai Ren, Smith Claire E. L., Inglehearn Christopher F., Mighell Alan J., Elcock Claire, Poulter James A., Tischkowitz Marc, Davies Sally J., Sefiani Abdelaziz, Mironov Aleksandr A., Newman William G., Waterham Hans R., van Camp Guy Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6 American journal of human genetics 2015;97 (4):535-545 [PubMed]
- Ebberink Merel S., Mooijer Petra A. W., Gootjes Jeannette, Koster Janet, Wanders Ronald J. A., Waterham Hans R. Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder Human mutation 2011;32 (1):59-69 [PubMed]
- Ebberink Merel S., Koster Janet, Visser Gepke, van Spronsen Francjan, Stolte-Dijkstra Irene, Smit G. Peter A., Fock Johanna M., Kemp Stephan, Wanders Ronald J. A., Waterham Hans R. A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11 beta gene Journal of medical genetics 2012;49 (5):307-313 [PubMed]
- Barøy Tuva, Koster Janet, Strømme Petter, Ebberink Merel S., Misceo Doriana, Ferdinandusse Sacha, Holmgren Asbjørn, Hughes Timothy, Merckoll Else, Westvik Jostein, Woldseth Berit, Walter John, Wood Nick, Tvedt Bjørn, Stadskleiv Kristine, Wanders Ronald J. A., Waterham Hans R., Frengen Eirik A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform Human molecular genetics 2015;24 (20):5845-5854 [PubMed]
- Ferdinandusse Sacha, Falkenberg Kim D., Koster Janet, Mooyer Petra A., Jones Richard, van Roermund Carlo W. T., Pizzino Amy, Schrader Michael, Wanders Ronald J. A., Vanderver Adeline, Waterham Hans R. ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism Journal of medical genetics 2017;54 (5):330-337 [PubMed]
Research programmes
Prof. PhD H.R. Waterham (Functional Genetics of Metabolic Diseases)
Isoprenoid biosynthesis defects
After identification of the underlying genetic defect in several disorders of cholesterol biosynthesis, we have shifted our research focus primarily to pathogenetic aspects of the inflammatory metabolic disorder mevalonate kinase deficiency (MKD), which is characterized by recurring episodes of inflammation and high fever. In the past years we reported the mutational spectrum in MKD (60 patients) and demonstrated that many mutations have an effect primarily on MK protein stability and folding. We furthermore showed that the enzyme defect in MKD results in a (temporary) defect of geranylgeranylation inducing a marked increase in the expression and secretion of the proinflammatory cytokine IL1-beta. Biochemical studies with cells of MKD patients using specific enzyme inhibitors and supplementation of intermediate isoprenoids indicated that such compounds may provide therapeutic treatment options for MKD patients. We are currently studying several mouse models for this disease (generated by ourselves) to get insight into the pathophysiology underlying the inflammation and to evaluate potential therapeutic interventions in an in vivo setting based on our previous in vitro data. Our studies will provide insight into the metabolic regulation of innate immunity. Peroxisome biogenesis defects This line focusses on the identification and characterization of defects in human peroxisome biogenesis and on developing therapeutic approaches for patients with relatively mild peroxisomal disease. We developed an efficient genetic complementation screen, with which we have assigned cell lines from >600 different patients with a defect in peroxisome biogenesis to different genetic complementation groups followed by characterization of the gene defects. Among these cell lines we identified several cell lines that display defects in peroxisome division, and thus constitute a novel group of peroxisomal disorders, for which the underlying gene defects have been identified and characterized. We are currently studying the effect of different treatments on the restoration of peroxisome biogenesis in cells of mildly affected patients and develop strategies to identify additional potential treatments. To be able to test the effect of such interventions in an in vivo setting, we recently generated a mouse model for a mild peroxisomal biogenesis disorder. Theme: Metabolic Disorders This research group participates in the Amsterdam Center for Metabolism
Faculty
PhD S. Ferdinandusse
PhD C.W.T. van Roermund
Prof. PhD R.J.A. Wanders
Others
PhD M.S. Ebberink
BEng J. Koster
BEng R. Ofman
BEng M. Turkenburg
Prof. PhD R.J.A. Wanders (Biochemistry & Enzymology of Metabolic Disorders)
Current research funding
- Europese Unie
- OxaluRx Inc.
- Stichting AMC Foundation (Vrijgesteld)
- Stichting Stofwisselkracht