| Research theme | Isoprenoid biosynthesis defects |
|---|---|
| Principal Investigator | Dr. Hans R. Waterham, associate professor |
| Group members | Dr. Merel S. Ebberink, PhD Marjolein Turkenburg, BSc Janet Koster, BSc |
The isoprenoid biosynthesis pathway generates a variety of bioactive molecules, i.e. sterol and nonsterol isoprenoids, which play pivotal roles in a wide range of essential cellular processes including growth, differentiation, glycosylation, isoprenylation and various signal transduction pathways. This research program aims to study human isoprenoid/cholesterol biosynthesis, to identify and characterize inherited defects of this pathway, and to study the pathophysiological consequences of such defects. Previously we identified and characterized several defects in the isoprenoid biosynthesis pathway, most of which affecting in particular the biosynthesis of cholesterol. In 1999, we resolved the genetic basis of the autoinflammatory disorder Hyperimmunoglobulinemia D and Periodic Fever Syndrome (HIDS), which turned out to be related to the metabolic disorder mevalonic aciduria, both caused by a deficiency of mevalonate kinase (MKD), a key enzyme in the isoprenoid biosynthesis pathway. This finding linked this essential metabolic pathway to the regulation of fever and inflammation and makes HIDS an attractive disorder to decipher regulatory mechanisms involved in the innate immune response. In the past 5 years, we have focused primarily on pathogenetic and pathophysiological aspects of MKD and sought to establish suitable model sytems to study these aspects in. For this purpose we have successfully generated different mouse models for HIDS which will allow us to extend our in vitro studies to an in vivo model. The ultimate aim of this research program is to develop rational therapeutic intervention options for patients with HIDS and patients suffering from other disorders associated with inflammation based on the role of the isoprenoid biosynthesis pathway in the regulation of innate immunity.
Key publications
Houten, S.M., W.Kuis, M.Duran, T.J.de Koning, A.Royen-Kerkhof, G.J.Romeijn, J.Frenkel, L.Dorland, M.M.de Barse, W.A.Huijbers, G.T.Rijkers, H.R.Waterham, R.J.Wanders, and Poll-The BT. 1999. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat. Genet. 22:175-177.
Mandey, S.H., L.M.Kuijk, J.Frenkel, and H.R.Waterham. 2006. A role for geranylgeranylation in interleukin-1beta secretion. Arthritis Rheum. 54:3690-3695.
Schneiders, M.S., S.M.Houten, M.Turkenburg, R.J.A.Wanders, and H.R.Waterham. 2006. Manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency. Arthritis Rheum.54:2306-2313.
Mandey, S.H., M.S.Schneiders, J.Koster, and H.R.Waterham. 2006. Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. Hum. Mutat. 27:796-802.
Waterham, H.R. 2006. Defects of cholesterol biosynthesis. FEBS Lett. 580:5442-5449.