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

To accelerate the biological annotation of novel genes discovered in sequen ced regions of mammalian genomes, we are creating large deletions in the mo use 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 orth ologous sequences, codes for nine putative genes. Mice homozygous for the d eletion had a variety of abnormalities, including severe hypertriglyceridem ia. hepatic and cardiac enlargement, growth retardation, and premature mort ality. 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 hypertriglyceridemi a in humans. A series of mouse BAC and human YAC transgenes covering differ ent intervals of the 450-kb deleted region were assessed for their ability to complement the deletion induced abnormalities. These studies revealed th at OCTN2, a gene recently shown to play a role in carnitine transport, was able to correct the triglyceride abnormalities. The discovery of this previ ously unappreciated relationship between OCTN2, carnitine, and hepatic trig lyceride production is of particular importance because of the clinical con sequence of hypertriglyceridemia and the paucity of genes known to modulate triglyceride secretion.