Germline mutations in the fumarate hydratase gene (FH) are responsible for the susceptibility to hereditary leiomyomatosis and renal cell cancer (HLRCC).HLRCC is the autosomal dominant predisposition to the development of cutaneous and uterine leiomyomas (smooth muscle) and renal cell cancer.FH catalyzes the conversion of furnarate to malate in the Krebs cycle.Using direct sequencing, we have identified 34 different FH mutations in 56 HLRCC families.It has been hypothesized that FH deficient cells become resistant to certain apoptotic signals and/or activate a pseduohypoxic response.To investigate the proposed mechanism, we investigated the gene expression in human embryonic kidney (HEK293) cells and smooth muscle cell transfected with FH specific small interference RNA (FH-siRNA).First, we examined the expression of hypoxia-responsive genes by using a real time PCR based human hypoxia signaling pathway array containing 84 genes involved in stress, signal transduetion, protein metabolism, cell growth, apoptosis, and transcription factors (SuperArray Bioscience, Frederick, MD).RNA samples in triplicates from HEK293 cells transfected with FH-siRNA and negative control siRNA were analyzed.Of the 84 hypoxia signaling pathway genes only baculovirus protein p35 (Bire5) showed significant differences.HEK293 cells transfected with FH-siRNA, demonstrated 2.9 fold down expression of Birc5 compared with control-siRNA (P=0.03).