Description

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
StatusActive
Effective start/end date1/01/06 → …

ID: 170674