PMID- 10655497
OWN - NLM
STAT- MEDLINE
DCOM- 20000302
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 97
IP  - 3
DP  - 2000 Feb 1
TI  - Genomic interval engineering of mice identifies a novel modulator of triglyceride
      production.
PG  - 1137-42
AB  - 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.
FAU - Zhu, Y
AU  - Zhu Y
AD  - Genome Sciences Department, Lawrence Berkeley National Laboratory, One Cyclotron 
      Road, Berkeley, CA 94720, USA.
FAU - Jong, M C
AU  - Jong MC
FAU - Frazer, K A
AU  - Frazer KA
FAU - Gong, E
AU  - Gong E
FAU - Krauss, R M
AU  - Krauss RM
FAU - Cheng, J F
AU  - Cheng JF
FAU - Boffelli, D
AU  - Boffelli D
FAU - Rubin, E M
AU  - Rubin EM
LA  - eng
GR  - NIH 18574/PHS HHS/United States
GR  - NIH 50590/PHS HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Carrier Proteins)
RN  - 0 (Lipoproteins, VLDL)
RN  - 0 (Membrane Proteins)
RN  - 0 (Organic Cation Transport Proteins)
RN  - 0 (SLC22A5 protein, human)
RN  - 0 (Solute Carrier Family 22 Member 5)
RN  - 0 (Triglycerides)
RN  - S7UI8SM58A (Carnitine)
SB  - IM
MH  - Animals
MH  - Carnitine/metabolism
MH  - Carrier Proteins/genetics/*physiology
MH  - Chromosome Mapping
MH  - Chromosome Walking
MH  - Chromosomes, Human, Pair 5/genetics
MH  - Genetic Complementation Test
MH  - Humans
MH  - Hypertriglyceridemia/*genetics/metabolism
MH  - Lipoproteins, VLDL/metabolism
MH  - Liver/metabolism
MH  - Membrane Proteins/genetics/*physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - *Organic Cation Transport Proteins
MH  - Phenotype
MH  - Sequence Deletion
MH  - Solute Carrier Family 22 Member 5
MH  - Species Specificity
MH  - Triglycerides/*metabolism
PMC - PMC15548
EDAT- 2000/02/03 09:00
MHDA- 2000/03/04 09:00
CRDT- 2000/02/03 09:00
PHST- 2000/02/03 09:00 [pubmed]
PHST- 2000/03/04 09:00 [medline]
PHST- 2000/02/03 09:00 [entrez]
AID - 10.1073/pnas.97.3.1137 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1137-42. doi: 10.1073/pnas.97.3.1137.