Human Molecular Genetics Advance Access published online on December 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi457
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1 Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
* To whom correspondence should be addressed. Glycerol kinase deficiency (GKD) is an X-linked inborn error of metabolism with metabolic and neurologic crises. Liver shows the highest level of glycerol kinase (GK) activity in humans and mice. Absence of genotype-phenotype correlations in patients with GKD indicate 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 the overall gene expression profile of the KO mice was different from that of WT. Real time PCR confirmed differences for selected genes. Functional gene enrichment analysis was used to find 56 increased and 37 decreased gene functional categories. Pathway Assist 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 SREBP-1c, ChREBP, HNF-4
Received October 6, 2005
Revised December 12, 2005
Accepted December 12, 2005
Article
Targeted disruption of glycerol kinase gene in mice: expression analysis in liver shows alterations in network partners related to glycerol kinase activity
Nicole K. MacLennan 1,
Lola Rahib 2,
Cynthia Shin 1,
Zixing Fang 3,
Steve Horvath 3,
Jason Dean 4,
James C. Liao 4,
Edward R.B. McCabe 5,
and
Katrina M. Dipple 6 *
2 Department of Biomedical Engineering, Henry Samueli School of Engineering and Applied Sciences at UCLA, Los Angeles, California 90095, USA
3 Department of Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA; Department of Human Genetics, the David Geffen School of Medicine, Los Angeles, California 90095, USA
4 Department of Chemical and Biomolecular Engineering, Henry Samueli School of Engineering and Applied Sciences, at UCLA, Los Angeles, California 90095, USA
5 Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA; Department of Human Genetics, the David Geffen School of Medicine, Los Angeles, California 90095, USA
6 Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA; Department of Biomedical Engineering, Henry Samueli School of Engineering and Applied Sciences at UCLA, Los Angeles, California 90095, USA; Department of Human Genetics, the David Geffen School of Medicine, Los Angeles, California 90095, USA
Katrina M. Dipple, E-mail: kdipple{at}mednet.ucla.edu
Abstract 
, and PPAR-, had increased activity in the Gyk KO mice compared with WT mice; while SREBP-2 was less active in the Gyk KO mice. These studies show that Gyk deletion causes alterations in gene expression of genes in several regulatory networks and is the first time NCA has been used to expand on microarray data from a mouse knockout model of a human disease.
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