Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency in Mice

Abstract

ABSTRACT. A murine model for short-chain acyl-coenzyme A dehydrogenase (SCAD) deficiency has been identified and characterized in BALBJcByJ mice. These mice have undetectable SCAD activity, severe organic aciduria; excreting ethylmalonic and methylsuccinic acids and Nbutyrylglycine, and develop a fatty liver upon fasting or dietary fat challenge. The mutant mice develop hypoglycemia after an 18-h fast, and have elevated urinary and muscle butyrylcarnitine concentrations. Most of these findings parallel those of human disorders associated with SCAD deficiency and other P-oxidation defects. This mouse model presents important opportunities to investigate the biology of mammalian fatty acid metabolism and the related human diseases. (Pediatr Res 25:38-43, 1989) Abbreviations SCAD, short-chain acyl-CoA dehydrogenase MCAD, medium-chain acyl-CoA dehydrogenase MCT, medium-chain triglycerides Deficiency of SCAD has been described recently in humans (1-4). The most severe form of this disorder is characterized by patients with episodes of metabolic acidosis, nonketotic hypoglycemia, and short-chain dicarboxylic aciduria. The clinical outcomes range from normalcy to unexpected death in homozygotes. Lately, sudden infant death syndrome and Reye's-like syndrome have been linked to defects in P-oxidation of fatty acids (5-7). Other recent studies have demonstrated that a secondary carnitine deficiency associated with the organic acidemia appears involved in the pathogenesis of the episodic events of these disorders (1,4,8). Overall, these diseases appear complex.We have a program to screen mice for inherited metabolic diseases (9) to develop models for investigating the pathogenesis and treatment of these disorders. In the course of screening mutant mice for organic acidurias using gas chromatographymass spectrometry, we discovered a subline of BALB/c mice (BALB/cByJ) that excreted unusually large concentrations of ethylmalonic and methylsuccinic acids and N-butyrylglycine. Butyryl-CoA dehydrogenase activity and electrophoretic mobility are used as a genetic marker for the Bcd-1 locus on mouse 38chromosome 5 (10). Subsequently, we learned that BALB/cByJ mice were found to have no detectable butyryl-CoA dehydrogenase activity by this marker assay (10). The null allele of these mice was designated Bcd-1" and was distinctly different from the normal activity associated with the Bcd-lb allele of BALB/cJ or BALB/cBy mice. To investigate the enzymatic defect and the resulting metabolic consequences, we performed a series of experiments using BALB/c By (Y) mice as controls and the BALB/ c ByJ (J) mutant mice. MATERIALS AND METHODSMice. BALB/cBy and BALB/cByJ mice were purchased from The Jackson Laboratory, (Bar Harbor, ME) and propagated at the Baylor College of Medicine (Houston, TX). All mice were maintained on Wayne rodent food no. 8640 (Wayne Pet Food Division, Continental Grain Co., Chicago, IL) and water ad libitum. Heterozygous mice were produced by crossing a Y female with a J male.Biochemistry. Urinary organic acids were ...

Disruption of Mitochondrial β-Oxidation of Unsaturated Fatty Acids in the 3,2-trans-Enoyl-CoA Isomerase-deficient Mouse

“…3). Triglyceride storage in the liver described here for the eci mouse has also been observed in SCAD-deficient mice (29). Both the unchallenged eci Ϫ/Ϫ and the scad Ϫ/Ϫ mouse are clinically asymptomatic, different from the SCAD deficiency in human, characterized by severe clinical symptoms.…”

“…Affected individuals develop a pathological phenotype only when an enhanced energy requirement must be covered by mitochondrial fatty acid ␤-oxidation, e.g. during prolonged fasting (29).…”

Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse

“…This is because deficiency in FAO not only reduces fat-derived energy supply but also leads to accumulation of fatty acid substrates or metabolites in the blood and other extra-cellular fluid compartment, in cytoplasm, and in mitochondria. Because CPT-1 is the rate-limiting enzyme for mitochondrial LCFA β-oxidation important in gametogenesis and embryogenesis [29][30][31], it is not surprising that, among available mouse models with enzyme deficiencies of FAO, a severe phenotype, or homozygous lethality is found in mice deficient in either CPT-1a [10] or CPT-1b (this study), in contrast to those with homozygous deficiency of any one of the four fatty acyl-CoA dehydrogenases (ACADs), which include very-long-, long-, medium-, and short-chain acyl-CoA dehydrogenases (VLCAD [32]; LCAD [33], MCAD [34]; and SCAD [35,36]). Also, among the four mouse models with deficiency in one of the ACADs, LCAD−/ − mice have the most severe phenotype including fatty liver, fasting and cold intolerance and gestational loss [33].…”

Misfolding, Degradation, and Aggregation of Variant Proteins

“…26) and from SCAD normal (BALB/cA, ϩ/ϩ) mouse liver as previously described (27,28) and suspended in mannitol buffer (250 mmol/liter mannitol, 25 mmol/liter sucrose, 10 mmol/liter Tris-HCL, pH 7.8, containing 0.1 mmol/liter EDTA) at 30 mg of protein/ ml. One volume of freshly prepared mitochondria was mixed with two volumes of the transcription/translation reaction and incubated at appropriate temperatures (26, 37, or 41°C).…”