Prof. dr. H.R. Waterham

Main activities
Patient care, Research, Teaching
Functional genetics, Clinical Laboratory Geneticist
Focus of research

Functional genetics and molecular biology of metabolic disorders in general but with focus on inborn errors of isoprenoid/cholesterol biosynthesis and peroxisome biogenesis.


Key publications
  • Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Guaoua S, Vandeweyer G, Urquhart JE, Chandler KE, Williams SG, Roberts NA, El Alloussi M, Black GC, Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch SA, Cooper N, Ong KR, Smith CEL, Inglehearn CF, Mighell AJ, Elcock C, Poulter JA, Tischkowitz M, Davies SJ, Sefiani A, Mironov AA, Newman WG, Waterham HR, van Camp G, Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6. AM J HUM GENET 2015;97 (4):535-545 [PubMed]
  • Ebberink MS, Mooijer PAW, Gootjes J, Koster J, Wanders RJA, Waterham HR, Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder. HUM MUTAT 2011;32 (1):59-69 [PubMed]
  • Ebberink MS, Koster J, Visser G, van Spronsen F, Stolte-Dijkstra I, Smit GPA, Fock JM, Kemp S, Wanders RJA, Waterham HR, A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11 beta gene. J MED GENET 2012;49 (5):307-313 [PubMed]
  • Barøy T, Koster J, Strømme P, Ebberink MS, Misceo D, Ferdinandusse S, Holmgren A, Hughes T, Merckoll E, Westvik J, Woldseth B, Walter J, Wood N, Tvedt B, Stadskleiv K, Wanders RJA, Waterham HR, Frengen E, A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform. HUM MOL GENET 2015;24 (20):5845-5854 [PubMed]
  • Ferdinandusse S, Falkenberg KD, Koster J, Mooyer PA, Jones R, van Roermund CWT, Pizzino A, Schrader M, Wanders RJA, Vanderver A, Waterham HR, ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism. J MED GENET 2017;54 (5):330-337 [PubMed]
All Publications
Research programmes

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

Prof. dr. H.R. Waterham
Dr. S. Ferdinandusse PhD
Dr. C.W.T. van Roermund
Prof. dr. R.J.A. Wanders

PhD Students
S. Chornyi
F.A. Politiek

Dr. M.S. Ebberink PhD
Ing. J. Koster
Ing. R. Ofman
Ing. M. Turkenburg

Prof. dr. R.J.A. Wanders (Biochemistry & Enzymology of Metabolic Disorders)

Other research related activities
  • Membership of editorial board / Editorship, HUMAN MUTATION
  • Membership of editorial board / Editorship, MOLECULAR GENETICS AND METABOLISM
  • Membership of medical or scientific committee, VKGL (Dutch Society for Clinical Genetic Laboratory Testing), Board member (treasurer)
Current research funding
  • AMC
  • Europese Unie
  • OxaluRx Inc.
  • Stichting AMC Foundation (Vrijgesteld)
  • Stichting Stofwisselkracht
  • ZonMw