期刊
MOLECULAR GENETICS AND METABOLISM
卷 86, 期 1-2, 页码 179-187出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2005.07.021
关键词
carnitine palmitoyltransferase-1; inborn error of metabolism; mouse model; gene targeting; lethal trait
资金
- NCI NIH HHS [P30-CA-13148] Funding Source: Medline
- NCRR NIH HHS [R01-RR-02599] Funding Source: Medline
- NHLBI NIH HHS [T32-HL-007918] Funding Source: Medline
- NIDDK NIH HHS [P30-DK-56336] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P30CA013148] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [R01RR002599] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL007918] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK056336] Funding Source: NIH RePORTER
To better understand carnitine palmitoyltransferase la (liver isoform, gene = Cpt-1a, protein = CPT-1a) deficiency in human disease, we developed a gene knockout mouse model. We used a replacement gene targeting strategy in ES cells that resulted in the deletion of exons 11-18, thus producing a null allele. Homozygous deficient mice (CPT-1 a -/-) were not viable. There were no CPT-1a -/- pups, embryos or fetuses detected from day 10 of gestation to term. FISH analysis demonstrated targeting vector recombination at the expected single locus on chromosome 19. The inheritance pattern from heterozygous matings was skewed in both C57BL/6NTac, 129S6/SvEvTac (136; 129 mixed) and 129S6/SvEvTac (129 coisogenic) genetic backgrounds biased toward CPT-1a +/- mice (> 80%). There was no sex preference with regard to germ-line transmission of the mutant allele. CPT-1a +/- mice had decreased Cpt-1a mRNA expression in liver, heart, brain, testis, kidney, and white fat. This resulted in 54.7% CPT-1 activity in liver from CPTI a +/- males but no significant difference in females as compared to CPT-1a +/+ controls. CPT-1a +/- mice showed no fatty change in liver and were cold tolerant. Fasting free fatty acid concentrations were significantly elevated, while blood glucose concentrations were significantly lower in 6-week-old CPT-1a +/- mice compared to controls. Although the homozygous mutants were not viable, we did find some aspects of haploinsufficiency in the CPT-1a +/- mutants, which will make them an important mouse model for studying the role of CPT-1a in human disease. (c) 2005 Elsevier Inc. All rights reserved.
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