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Human Molecular Genetics Advance Access published online on November 30, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi431
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received August 31, 2005
Accepted November 17, 2005

Article

Distinct Expression Profile in Fumarate Hydratase-Deficient Uterine Fibroids

Sakari Vanharanta 1, Patrick J. Pollard 2, Heli J. Lehtonen 1, Päivi Laiho 1, Jari Sjöberg 3, Arto Leminen 3, Kristiina Aittomäki 4, Johanna Arola 5, Mogens Kruhoffer 6, Torben F. ørntoft 6, Ian P. Tomlinson 2, Maija Kiuru 1, Diego Arango 1, and Lauri A. Aaltonen 1 *

1 Department of Medical Genetics, P.O. Box 63 (Haartmaninkatu 8), Biomedicum Helsinki, FIN-00014 University of Helsinki, Finland
2 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
3 Department of Obstetrics and Gynaecology, P.O. Box 22 (Haartmaninkatu 2), FIN-00014 University of Helsinki, Finland
4 Department of Clinical Genetics, P.O. Box 140 (Haartmaninkatu 2 B), FIN-00029 Helsinki University Central Hospital, Finland
5 Department of Pathology, P.O. Box 21 (Haartmaninkatu 3), FIN-00014 University of Helsinki, Finland
6 Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark

* To whom correspondence should be addressed.
Lauri A. Aaltonen, E-mail: lauri.aaltonen{at}helsinki.fi


  Abstract

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 (TCA) cycle, cause Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC); 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 to 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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