Genomic interval engineering of mice identifies a novel modulator of triglyceride production.

Abstract

To accelerate the biological annotation of novel genes discovered in sequenced regions of mammalian genomes, we are creating large deletions in the mouse genome targeted to include clusters of such genes. Here we describe the targeted deletion of a 450-kb region on mouse chromosome 11, which, based on computational analysis of the deleted murine sequences and human 5q orthologous sequences, codes for nine putative genes. Mice homozygous for the deletion had a variety of abnormalities, including severe hypertriglyceridemia, hepatic and cardiac enlargement, growth retardation, and premature mortality. Analysis of triglyceride metabolism in these animals demonstrated a several-fold increase in hepatic very-low density lipoprotein triglyceride secretion, the most prevalent mechanism responsible for hypertriglyceridemia in humans. A series of mouse BAC and human YAC transgenes covering different intervals of the 450-kb deleted region were assessed for their ability to complement the deletion induced abnormalities. These studies revealed that OCTN2, a gene recently shown to play a role in carnitine transport, was able to correct the triglyceride abnormalities. The discovery of this previously unappreciated relationship between OCTN2, carnitine, and hepatic triglyceride production is of particular importance because of the clinical consequence of hypertriglyceridemia and the paucity of genes known to modulate triglyceride secretion.

• Authors: Y Zhu, M C Jong, K A Frazer, E Gong, R M Krauss, J F Cheng, D Boffelli, E M Rubin
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 97 Issue 3 Pg. 1137-42 (Feb 01 2000) ISSN: 0027-8424 [Print] United States
• PMID: 10655497 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carrier Proteins
• Lipoproteins, VLDL
• Membrane Proteins
• Organic Cation Transport Proteins
• SLC22A5 protein, human
• Solute Carrier Family 22 Member 5
• Triglycerides
• Carnitine

Topics

• Animals
• Carnitine (metabolism)
• Carrier Proteins (genetics, physiology)
• Chromosome Mapping
• Chromosome Walking
• Chromosomes, Human, Pair 5 (genetics)
• Genetic Complementation Test
• Humans
• Hypertriglyceridemia (genetics, metabolism)
• Lipoproteins, VLDL (metabolism)
• Liver (metabolism)
• Membrane Proteins (genetics, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Organic Cation Transport Proteins
• Phenotype
• Sequence Deletion
• Solute Carrier Family 22 Member 5
• Species Specificity
• Triglycerides (metabolism)