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Homozygous carnitine palmitoyltransferase 1a (liver isoform) deficiency is lethal in the mouse
Lara R Nyman1, Keith B Cox, Charles L Hoppel
1Department of Genetics, University of Alabama at Birmingham, USA.
Abstract:
To better understand carnitine palmitoyltransferase 1a (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-1a -/-) 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 (B6;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 CPT-1a +/- 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.
Insights
Carnitine palmitoyltransferase 1a (CPT-1a) deficiency causes non-viable homozygous mice. Heterozygous CPT-1a +/- mice exhibit metabolic changes, indicating haploinsufficiency and serving as a model for human disease.
Area of Science:
- Genetics
- Biochemistry
- Physiology
Background:
- Carnitine palmitoyltransferase 1a (CPT-1a) is crucial for long-chain fatty acid oxidation.
- Understanding CPT-1a deficiency in human disease requires appropriate animal models.
Purpose of the Study:
- To develop a gene knockout mouse model for CPT-1a deficiency.
- To investigate the viability and phenotype of CPT-1a deficient mice.
Main Methods:
- Gene targeting in ES cells to create a CPT-1a null allele (exons 11-18 deletion).
- Analysis of homozygous (CPT-1a -/-) and heterozygous (CPT-1a +/-) mice across different genetic backgrounds.
- Assessment of Cpt-1a mRNA expression, CPT-1 activity, metabolic parameters, and cold tolerance.
Main Results:
- Homozygous CPT-1a -/- mice were not viable during embryonic development.
- Heterozygous CPT-1a +/- mice showed skewed inheritance patterns (>80%) and reduced Cpt-1a mRNA expression in multiple tissues.
- CPT-1a +/- mice exhibited decreased liver CPT-1 activity (males), elevated fasting free fatty acids, and lower blood glucose, but no fatty liver or cold intolerance.
Conclusions:
- CPT-1a deficiency leads to embryonic lethality in mice.
- CPT-1a +/- mice display haploinsufficiency with distinct metabolic alterations.
- This CPT-1a +/- mouse model is valuable for studying CPT-1a's role in human metabolic diseases.
