Human Molecular Genetics Advance Access originally published online on November 30, 2005
Human Molecular Genetics 2006 15(1):97-103; doi:10.1093/hmg/ddi431
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Distinct expression profile in fumarate-hydratase-deficient uterine fibroids
1Department of Medical Genetics, PO Box 63 (Haartmaninkatu 8), Biomedicum Helsinki, 2Department of Obstetrics and Gynaecology, PO Box 22 (Haartmaninkatu 2), 3Department of Clinical Genetics, PO Box 140 (Haartmaninkatu 2B) and 4Department of Pathology, PO Box 21 (Haartmaninkatu 3), University of Helsinki, FIN-00014 Helsinki, Finland, 5Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK and 6Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
* To whom correspondence should be addressed. Tel: +358 91911; Fax: +358 919125105; Email: lauri.aaltonen{at}helsinki.fi
Received August 31, 2005; Accepted November 17, 2005
Defects in mitochondrial enzymes predispose to severe developmental defects as well as tumorigenesis. Heterozygous germline mutations in the nuclear gene encoding fumarate hydratase (FH), an enzyme catalyzing the hydration of fumarate in the Krebs tricarboxylic acid cycle, cause hereditary leiomyomatosis and renal cell cancer; yet the connection between disruption of mitochondrial metabolic pathways and neoplasia remains to be discovered. We have used an expression microarray approach for studying differences in global gene expression pattern caused by mutations in FH. Seven uterine fibroids carrying FH mutations were compared with 15 fibroids with wild-type FH. The two groups showed markedly different expression profiles, and multiple differentially expressed genes were detected. The most significant increase in FH mutants was seen in the expression of carbohydrate metabolism- and glycolysis-related genes. Other significantly up-regulated gene categories in FH mutants were, for example, iron ion homeostasis and oxidoreduction. Genes with lower expression in FH-mutant fibroids belonged to groups such as extracellular matrix, cell adhesion, muscle development and cell contraction. We show that FH mutations alter significantly the expression profiles of fibroids, most strikingly increasing the expression of genes involved in glycolysis.
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