Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse.
Carnitine palmitoyltransferase-1 (CPT-1) catalyzes the rate-limiting step of mitochondrial beta-oxidation of long chain fatty acids (LCFA), the most abundant fatty acids in mammalian membranes and in energy metabolism. Human deficiency of the muscle isoform CPT-1b is poorly understood. In the current study, embryos with a homozygous knockout of Cpt-1b were lost before embryonic day 9.5-11.5. Also, while there were normal percentages of CPT-1b+/- pups born from both male and female CPT-1b+/- mice crossed with wild-type mates, the number of CPT-1b+/- pups from CPT-1b+/- breeding pairs was under-represented (63% of the expected number). Northern blot analysis demonstrated approximately 50% Cpt-1b mRNA expression in brown adipose tissue (BAT), heart and skeletal muscles in the CPT-1b+/- male mice. Consistent with tissue-specific expression of Cpt-1b mRNA in muscle but not liver, CPT-1+/- mice had approximately 60% CPT-1 activity in skeletal muscle and no change in total liver CPT-1 activity. CPT-1b+/- mice had normal fasting blood glucose concentration. Consistent with expression of CPT-1b in BAT and muscle, approximately 7% CPT-1b+/- mice (n=30) developed fatal hypothermia following a 3h cold challenge, while none of the CPT-1b+/+ mice (n=30) did. With a prolonged cold challenge (6h), significantly more CPT-1b+/- mice developed fatal hypothermia (52% CPT-1b+/- mice vs. 21% CPT-1b+/+ mice), with increased frequency in females of both genotypes (67% female vs. 38% male CPT-1b+/- mice, and 33% female vs. 8% male CPT-1b+/+ mice). Therefore, lethality of homozygous CPT-1b deficiency in the mice is consistent with paucity of human cases.
Ji
Shaonin
S
Department of Genetics, University of Alabama at Birmingham, USA.
You
Yun
Y
Kerner
Janos
J
Hoppel
Charles L
CL
Schoeb
Trenton R
TR
Chick
Wallace S H
WS
Hamm
Doug A
DA
Sharer
J Daniel
JD
Wood
Philip A
PA
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000172:deficiency* / Q000235:genetics; D020964:Embryo Loss; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D007035:Hypothermia / Q000235:genetics* / Q000401:mortality; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology*; D009928:Organ Specificity
D007527:Isoenzymes; D002334:Carnitine O-Palmitoyltransferase