Human Molecular Genetics Advance Access originally published online on December 20, 2005
Human Molecular Genetics 2006 15(3):405-415; doi:10.1093/hmg/ddi457
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Targeted disruption of glycerol kinase gene in mice: expression analysis in liver shows alterations in network partners related to glycerol kinase activity
1Department of Pediatrics, 2Department of Biostatistics and 3Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA, 4Department of Biomedical Engineering and 5Department of Chemical and Biomolecular Engineering, Henry Samueli School of Engineering and Applied Sciences at UCLA, Los Angeles, CA 90095, USA
* To whom correspondence should be addressed at: Department of Human Genetics, David Geffen School of Medicine at UCLA, Gonda 5506B, 695 Charles E. Young Drive South, Los Angeles, CA 90095-7088, USA. Tel: +1 3108251997; Fax: +1 3107945446; Email: kdipple{at}mednet.ucla.edu
Received October 6, 2005; Accepted December 9, 2005
Glycerol kinase deficiency (GKD) is an X-linked inborn error of metabolism with metabolic and neurological crises. Liver shows the highest level of glycerol kinase (GK) activity in humans and mice. Absence of genotype–phenotype correlations in patients with GKD indicates the involvement of modifier genes, including other network partners. To understand the molecular pathogenesis of GKD, we performed microarray analysis on liver mRNA from neonatal glycerol kinase (Gyk) knockout (KO) and wild-type (WT) mice. Unsupervised learning revealed that the overall gene expression profile of the KO mice was different from that of WT. Real-time PCR confirmed the differences for selected genes. Functional gene enrichment analysis was used to find 56 increased and 37 decreased gene functional categories. PathwayAssist analysis identified changes in gene expression levels of genes involved in organic acid metabolism indicating that GK was part of the same metabolic network which correlates well with the patients with GKD having metabolic acidemia during their episodic crises. Network component analysis (NCA) showed that transcription factors sterol regulatory element-binding protein (SREBP)-1c, carbohydrate response element-binding protein (ChREBP), hepatocyte nuclear factor-4 alpha (HNF-4
) and peroxisome proliferative-activated receptor-alpha (PPAR) had increased activity in the Gyk KO mice compared with WT mice, whereas SREBP-2 was less active in the Gyk KO mice. These studies show that Gyk deletion causes alterations in expression of genes in several regulatory networks and is the first time NCA has been used to expand on microarray data from a mouse KO model of a human disease.