Organic aciduria and butyryl CoA dehydrogenase deficiency in BALB/cByJ mice

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Biochemical Genetics, Vol.27, Nos. 1/2, 1989

Organic Aciduria and Butyryl CoA Dehydrogenase Deficiency In BALB/cByJ Mice Stephen P. Schiffer, 1 Michal Prochazka, 2 Peter F. Jezyk, 3 Thomas H. Roderick, 2 Marc Yudkoff, 4 and Donald F. Patterson 3

Received30 June 1988--Final 22 Sept. 1988

A metabolic screening program of inbred strains of mice has detected a marked organic aciduria in the BALB/cByJ strain. Gas chromatographic and mass spectrometric analysis identified large quantities of n-butyrylglycine plus lesser quantities of ethylmalonic acid. Crosses with the nonexcreting C57BL/6J strain indicate that this condition is inherited as an autosomal recessive trait. Independently from this screening a variant with no detectable enzyme activity of butyryl CoA dehydrogenase (BCD) in liver and kidney of the BALB/cByJ strain but not other BALB/c sublines was discovered. Data from a three-point cross indicated that the null variant maps to the structural locus for the enzyme, B c d - 1 , on chromosome 5. The findings indicate that a mutation at or near B c d - 1 in the BALB/cByJ strain resulted in a biochemical abnormality manifest as the BCD deficiency. It is concluded that accumulation of butyryl CoA due to a block in the oxidation of short-chain fatty acids results in an overproduction of organic metabolites leading to the observed organic aciduria. The fact that other BALB/c substrains do not exhibit this

This work was supported by NIH Grants RR02512 and GM32592 to the University of Pennsylvania and HD23168, NS 17752, and HD08536 to the Children's Hospital of Philadelphia, National Science Foundation Grant BSR 84-18828 to The Jackson Laboratory, and a Postdoctoral Fellowship from the Juvenile Diabetes Foundation International to Dr. Prochazka. ~Department of Anatomy and Cell Biology, Georgetown University School of Medicine, Washington, D.C. 20007. 2 The Jackson Laboratory, Bar Harbor, Maine 04609. 3 Section of Medical Genetics and Referral Center for Animal Models of Human Genetic Disease, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104. 4 ChiIdren's Hospital of Philadelphia, Pennsylvania 19104. 47 0006-2928/89/0200-0047506.00/0

© 1989 Plenum Publishing Corporation

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abnormality further suggests that this disorder reflects subline divergence within the BALB/c family. KEY WORDS: organicaciduria; BALB/cByJ;mousegenetics; butyrylCoA dehydrogenase,

short-chainfattyacid metabolism. INTRODUCTION Metabolic screening of animals using their urine is an easy and useful approach for detection of metabolic disorders that are of either genetic or acquired origins. As renal transport systems do not exist for most metabolites not normally found in measurable quantities in blood, even minute quantities in blood are concentrated to detectable levels in urine. In disorders in which normal metabolites accumulate to excessive levels, the concentrations usually exceed the renal threshold. Additionally, some disorders involve defects in the renal transport systems (Jezyk, 1983). Urine metabolic screening is feasible in mice since only small volumes are required to detect a wide range of compounds. Such testing is capable of detecting metabolic conditions that are subtle or subclinical without requiring the sacrifice of the animal. During a metabolic screening program of inbred and mutant strains of mice, a characteristic organic aciduria pattern was detected in all BALB/ cByJ mice tested but not in mice from 33 other strains. Independently of this program, a lack of activity of butyryl CoA dehydrogenase (BCD) was observed in liver and kidney extracts from BALB/cByJ mice but not other BALB/c sublines (Prochazka and Leiter, 1986). BCD is a mitochondrial enzyme which catalyzes the first dehydrogenation step in fatty acid /3oxidation with a specificity for C4-C6 acyl CoA substrates (Green et al., 1954). The structural locus, Bed-l, is located on chromosome 5 in the mouse (Seeley and Holmes, 1981). In this paper, we define the organic aciduria and present evidence that the lack of BCD activity maps to the structural gene Bed-! on chromosome 5. The combined data from both studies suggest that the enzyme abnormality and the organic aciduria observed in BALB/cByJ strain are both manifestations of a new mutation of the Bed-1 locus. MATERIALS AND METHODS Mouse Strains and Breeding Experiments

Urine samples were collected from 34 inbred strains of mice maintained at The Jackson Laboratory. Strains tested included AEJ/GnRk, A/J, AKR/J, BALB/cByJ, BALB/cJ, BALB/cWtBm, BDP/J, BUB/BnJ, CALB/Rk,

OrganicAciduriaand ButyrylCoA DehydrogenaseDeficiencyin Mice

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CASA/Rk, CBA/J, CE/J, C3HeB/FeJ, C57BL/6J, C58/J, DBA/2J, H R S / J , IS/CamRk, LP/J, MA/MyJ, MOLD/Rk, NZB/B1NJ, PERA/ Rk, P/J, RF/J, RIIIS/J, SEA/GnJ, SEC/1Re J, SF/CamRk, SJL/J, SM/J, ST/b J, ST/6J, SWR/J, and 129/J. For each strain, two or three males and females that were 7-14 weeks of age were tested. All mice were offered a standard rodent diet (Old Guilford Diet 96) and water ad libitum. Contact bedding consisted of pine shavings and all animals were maintained in rooms with a 12:12 light-dark cycle. BCD activity phenotypes were determined in strain BALB/cByJ and five other BALB/cBy sublines (provided by Dr. D. Bailey), BALB/cJ, BALB/ cWtBm, and C57BL/6J. In two separate studies, F~ hybrids (BALB/cByJ × C57BL/6J) and F 1 × BALB/cByJ first-backcross (BC1) offspring were analyzed to determine the mode of inheritance of the organic aciduria and the genetic basis of the BCD variant. Paper Chromatography

Paper chromatography was used for initial screening of the urine (Jczyk, 1979). Urine from each mouse was collected on a samplc strip of Whatman 3MM paper which was dried and stored in paraffin envelopes at room temperature. For analysis, disks were punched out of each sample strip using a paper punch, insertcd into a test sheet also of Whatman 3MM paper, and used for descending chromatography with butanol:acetic acid:water ( 12:3:5) as thc solvent. The sheets were dried thoroughly in a fumc hood and stained for organic acids using 4, 4'-bis diphenyl-dimcthyl amino carbinol. Gas Chromatography and Mass Spectrometry

Liquid urine samples for gas chromatography and mass spectrometry were eluted from sample strips using deionizcd distilled water and were stored at - 2 0 ° C until analyzed. Organic acids in these samples were identificd by gas-liquid chromatography (Cohn et al., 1978). An internal standard of hendecanedioic acid was addcd to each sample. Thc urine was acidified to pH 1 with 6 N HC1 and batch-extractcd twice with ether. The pooled ether extracts were evaporated to dryness in a screw-cap vial, appropriate amounts of N, O-bis(trimethylsilyl)trifluoroacctamidc and trimcthylchlorosilane were added, and the mixture was incubated at 60°C for 30 rain. The trimcthylsilyl derivatives thus formed wcrc dissolved in a small volume of ether and analyzed by gas-liquid chromatography on 3% OV-1 or OV-17 columns. Idcntifications were made by comparison with known standards by their calculated methylene units and/or by combined gas chromatography-mass spectrometry (GC-MS) (Tanaka et al., 1980).

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Mass spectrometry was done on a Finnigan 4021 G C - M S . Scans were taken from 80 to 500 a m u every 1.9 sec. The filament was at 70 eV, and the electron multiplier at f 5 0 0 V. Chromatography was done on a Supelcl 0.32 m m x 30 M D B - 5 column. The temperature program was 60°C for 3 min and then at 5 ° C / m i n to 275°C.

Metabolite Quantification Urine samples from four 8-week-old male BALB/cByJ and C57BL/6J mice were analyzed to quantify the excretion of specific metabolites. Metabolite concentrations were measured by gas-liquid chromatography as described above. Urine creatinine concentrations were measured by the Jaffe reaction (Hawk et al., 1954).

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Fig. 1. Tracings of gas chromatograms of organic acids from eluted urine samples taken from (A) BALB/cByJ, (B) C57BL/6J, (C) BALB/cJ, and (D) BALB/cWtBm. Compounds noted are (1) benzoate, (2) ethylmalonate, (3) succinate, (4) n-butyrylglycine, (5) a-ketoglutarate, (6)parahydroxyphenylpropionate, (7) hippurate, (8) citrate, and (9) internal standard.

Organic Aciduriaand ButyrylCoA DehydrogenaseDeficiency in Mice

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Homogenate Preparation

Fresh tissue was homogenized in 2 vol of 0.05 M Tris-HC1 (pH 8.0) buffer containing 0.1% Triton X-100 (Seeley and Holmes, 1981) and centrifuged at 28,000g for 30 rain at 4°C. Approximately 5-10 #1 of the supernatants was used for electrophoresis. Electrophoresis and Staining of Isozymes

For the purpose of analyzing a large number of samples for the linkage study, isoforms of BCD and D-amino oxidase (DAO) were analyzed by zone electrophoresis on cellulose acetate plates (Titan III, Helena Laboratories) and stained by an agar-overlay technique as described (Seeley and Holmes, 1981). The procedure for typing DAO isoforms was modified by using 0.09 M Tris-base/0.05 M boric acid/0.002 M NazEDTA (pH 8.3) as the running buffer. This resulted in a better resolution of the fast (A) and slow (B) anodally migrating isoform of DAO. For typing of structural isoforms of/3-glucuronidase (GUS), a method originally used for starch gel electrophoresis assay of GUS (Lalley and Shows, 1974) was adapted for cellulose acetate electrophoresis. Kidney extracts were run at 200 V for 40 rain in 0.02 M Tris-base/0.007 M citric acid (pH 7.1) buffer. Plates were stained by a histochemical method of Hyashi et al. (1964) including 1% of melted agar in the staining mixture for the overlay. The plates were incubated at 37°C until red-colored reaction product developed at the site of enzyme activity. RESULTS Paper chromatograms consistently detected a single prominent organic acid spot in BALB/cByJ urine. This compound has a RF slightly greater than that of the methylmalonic acid standard. Whereas both male and female BALB/ cByJ mice exhibit this organic aciduria, chromatograms of urine from other strains had either no detectable organic acids or small spots with different mobilites. Two other BALB/c substrains, BALB/cJ and BALB/cWtBm, also were tested and were distinctly different from the BALB/cByJ in having little or no organic acid in their urine. Figure 1 shows gas chromatograms of urine from male BALB/cByJ, C57BL/6J, BALB/cJ, and BALB/cWtBm mice. In the BALB/cByJ urine, the chromatogram was dominated by a large peak with a methylene unit number similar to that of butyrylglycine and had a smaller peak tentatively identified as ethylmalonate. The BALB/cJ urine had negligible amounts of organic acid, while BALB/cWtBm urine had low levels of several organic

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Fig. 2. Massspectrometricanalysisof majororganicacidsin urinefromBALB/cByJmice. Compoundsidentifiedare (A) n-butyrylglycineand (B) ethylmalonate. acids including succinate, a-ketoglutarate, hippurate, and citrate but lacked the peaks seen in BALB/cByJ. Urine from C57BL/6J mice had only trace amounts of organic acids. Figure 2 shows the mass spectrometric identification of the major compounds in the BALB/cByJ urine. The spectrum of the unknown compound matchec~ the library spectrum of n-butyrylglycine. Figure 2 also shows confirmation of the other peak as ethylmalonic acid. No identifying peaks for n-butyrylglycine or ethylmalonic acid were detected in the urine of C57BL/6J mice using gas-liquid chromatography. However, in urine from BALB/cByJ mice, the average concentration of n-butyrylglycine was 7668 mg/g of creatinine (range, 6737 to 9226) and that of ethylmalonic acid was 1426 mg/g of creatinine (range, 1310 to 1668). BALB/cByJ mice were crossed to nonexcreting C57BL/6J mice and the offspring were tested and backcrossed to BALB/cByJ mice. Table I shows the results of these genetic test crosses. All F] mice were negative for the organic aciduria pattern seen in BALB/cByJ mice. Exactly 50% of the backcross mice exhibited an organic aciduria pattern identical to that of the BALB/cByJ (9 of 20 females and 12 of 22 males). Figure 3 shows representative gas

Table I. Identification of Organic Aciduria Among (BALB/cByJ × C57BL/6J)F~ and the Backcross to BALB/cByJ a F~

Backcross

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Fig. 3. Tracings of gas chromatograms of organic acids from eluted u r i n e samples t a k e n from (A) ( B A L B / cByJ x C57BL/6J) F~ and (B) baekcross to BALB/cByJ (affected). Compounds noted are (1) ethylmalonate, (2) nbutyrylglycine, and (3) internal standard.

54

Sehiffer et

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Fig. 4. (A) Genetic variants of BCD determined by cellulose acetate electrophoresis of kidney extracts from C57BL/6J, Bcd-1 a (lanes 1 and 7); BALB/cJ Bcd-1 b (lanes 2 and 8); BALB/cByJ, Bcd-1 ° (lane 3); (C57BL/6J × BALB/cJ)F1, B c d - P / b (lane 4); (BALB/ cJ x BALB/cByJ) F1, Bcd-1 b/° (lane 5); (C57BL/6J × BALB/ cByJ)Fl, Bcd-1 a/° (lane 6). Arrow indicates the electrophoretic migration (cathode to anode). (B) Comparison of BCD activity in kidney extracts between BALB/cJ (lane 1), BALB/cByJ (lane 2), five different BALB/cBy sublines maintained separately from BALB/ cByJ (lanes 3-7), and BALB/cGrRk (lane 8).

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Organic Aciduria and Butyryl CoA Dehydrogenase Deficiency in Mice

55

chromatograms which confirm the presence of n-butyrylglycine and ethylmalonate in the urine of affected backcross mice and demonstrate their absence in the urine of the F1 mice. These findings are consistent with the conclusion that the underlying metabolic difference leading to the urinary excretion of large amounts of n-butyrylglycine in BALB/cByJ mice is inherited as an autosomal recessive trait. Lack of detectable BCD activity was observed in tissue extracts from all BALB/cByJ mice but not in mice of other strains maintained in Animal Resources at The Jackson Laboratory. Electrophoretic analysis of tissue extracts from BALB/cJ, BALB/cWtBm, and five other BALB/cBy sublines maintained separately in the research colonies at The Jackson Laboratory revealed a normal activity of the b form as expected for the "BALB/c" mice (Fig. 4). F1 hybrids between BALB/cByJ and BALB/cJ mice expressed the b allele, although the activity level (judged by the intensity of the histochemical staining) was reduced compared to that of the BALB/cJ parent. Hybrids between BALB/cByJ and C57BL/6J mice expressed only the a allele (characteristic for C57BL/6J), and not the b allele. These findings indicated a codominant inheritance of the BCD variant. Analysis of liver extracts from 24 mice produced by backcrossing (BALB/cJ × BALB/cByJ) F1 to BALB/ cByJ has shown a 1:1 segregation of the positive and negative BCD

Table II. Three-point Cross Analysis of the BCD "Null" Variant Locus a Bcd-1 b

Gus_s c

Dao-1 a

o a a b o a o a

a ab a ab a ab ab a

b ab b ab ab b b ab

x x

x ×

× x x ×

N

41 17 1 2 4 0 3 2 Total: 70

aThe genes from the left to the right are listed in their order from the centromere to the telomere on chromosome 5 (Lyon, 1987). All eight classes of genotype combinations expected in BCI [BALB/cByJ x ( B A L B / c B y J x C57BL/6J)F1] are shown. Recombinations are indicated by x. bo, "null" BCD phenotype in BALB/cByJ; a, fast anodally migrating isoform in C 5 7 B L / 6 J (see Fig. 4A). Ca, fast isoform in BALB/cByJ; b, slow isoform in C 5 7 B L / 6 J . aa, fast isoform in C 5 7 B L / 6 J ; b, slow isoform in BALB/cByJ.

56

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et

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phenotypes (12 positive:12 negative), which was consistent with a pattern expected for a single-gene mutation. To determine whether the null variant of BCD is associated with the structural locus Bed-1 on chromosome 5, a three-point cross analysis was performed using two other marker genes, Gus-s and Dao-l, linked to Bed-1. For this cross, the C57BL/6J strain was chosen because it differs from BALB/cByJ at all three loci. F1 hybrids were backcrossed to BALB/cByJ and kidney extracts from 70 BCI mice were typed for the three markers. The results summarized in Table II show that only the A form of BCD (determined by the a allele from C57BL/6J) can be detected in the BCDpositive BC~ mice. Moreover, the relative map distances between the markers Gus-s, Dao-1, and Bcd-1 calculated from the recombination frequencies obtained in this cross are in good agreement with the map distances between these loci reported previously (Seeley and Holmes, 1981; Lyon, 1987). Our data indicate that the null variant indeed maps (or is closely linked) to Bed-1. We propose a designation Bcd-1 ° for this new allele producing the "null" BCD phenotype in BALB/cByJ strain.

DISCUSSION Two independent discoveries lead to the conclusion that a mutation at or near the structural locus Bed-1 in BALB/cByJ mouse strain has resulted in a biochemical abnormality characterized by a lack of histochemically detectable BCD activity and organic aeiduria. The prominent urinary excretion by BALB/cByJ mice of n-butyrylglycine along with lesser amounts of ethylmalonic acid suggested a disorder involving short-chain fatty acid metabolism. Acylglycines are excreted in urine when corresponding acyl CoA's accumulate intracellularly (Kolvraa et al., 1980; Gregersen et al., 1986). The deficiency of BCD observed in this strain (Prochazka et al., 1986) that affects the first step in/3-oxidation of four-carbon straight-chain fatty acids will result in a block in the multistep conversion pathway of butyryl CoA to acetyl CoA. This will lead to a buildup of butyryl CoA in the cell. Presumably, excessive amounts of butyryl CoA in the mitochondria of BALB/cByJ mice are conjugated with glycine by glyeine-N-acylase, resulting in the formation of butyrylglycine and eventual excretion in urine (Kolvraa and Gregersen, 1986). Lesser amounts of the butyryl CoA would be carboxylated to ethylmalonyl CoA by propionyl CoA carboxylase and then hydrolyzed to ethylmalonic acid (Turnbull et al., 1984). Genetic analyses of the null variant are consistent with the assumption that the lack of BCD activity in BALB/cByJ is due to a mutation at the structural locus itself or at a cis-acting elosely linked regulatory locus which may affect the expression of Bcd-l. A recent brief report has described a similar enzyme deficiency in mice, although the strain

Organic Aeiduria and Butyryl CoA Dehydrogenase Deficiency in Mice

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was not identified and the presence or absence of clinical signs was not mentioned (Amendt et al., 1988). Most importantly, such an enzyme deficiency also has been described in human patients that were deficient in short-chain (butyryl) acyl CoA dehydrogenase (Turnbull et al., 1984; Bennett et al., 1985; Amendt et al., 1987; Coates et al., 1988). It is apparent that unlike human patients, where the BCD deficiency has serious clinical consequences, the mutation in BALB/cByJ mice does not seem to be deleterious. That the animals appear normal in the face of a disorder in fatty acid metabolism is not explained at this point. Two factors may be important to help maintain homeostasis in the affected mice. First, the rapid conjugation of butyryl CoA with glycine would reduce the chances of developing an acid-base imbalance due to an accumulation of endogenous acids. This, of course, would depend upon adequate mitochondrial levels of glycine-Nacylase. Second, adequate supplies of acetyl CoA to the citric acid cycle would still be produced during/3-oxidation of long-chain fatty acids. There are a few other examples of mutations affecting an enzyme activity in the laboratory mouse with no apparent adverse effects on viability or reproduction. These include the cytoplasmic malic enzyme (Lee et al., 1980; Sul et al., 1984), sorbitol dehydrogenase (Holmes et al., 1982), and glycerol-p-dehydrogenase (Prochazka et al., 1988). That the other BALB/c substrains and sublines studied did not exhibit the lack of BCD and the organic aciduria suggest that subline divergence has occurred at least since the Andervont branch of the BALB/c family split from the Scott branch (BALB/cJ) and the Green branch (BALB/cWtBm) (Potter, 1985). At The Jackson Laboratory, BALB/cByJ mice were transferred to the Animal Resources Facilities in 1975 and this subline has been separated for over 30 inbred generations from the sublines maintained in research colonies expressing the Bed-1 b allele at normal activity levels. Therefore, we conclude that the new mutation at Bed-1 occurred during this period. The Bcd-1 ° allele may be useful as a genetic marker for the BALB/cByJ strain. Also, this strain may be a valuable tool in biochemical studies on fatty acid oxidation as well as in studies on BCD at the molecular level. ACKNOWLEDGEMENTS We thank Stephen H. Langley and Patricia A. Norwood for valuable technical assistance. REFERENCES

Amendt,B. A., Greene,C., Sweetman,L., Cloherty,3. Shih,V., Moon,A., Teel,L., and Rhead, W. J. (1987). Short chain acyl-coenzymeA dehydrogenasedeficiency:Clinical and biochemicalstudiesin two patients.J. Clin. Invest. 79:1303.

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Amendt, B. A., Wood, P. A., Rhead, W. J., Millington, D. S., and Armstrong, D. (1988). Short chain acyl-coenzyme A dehydrogenase deficiency in mice: A murine model for B-oxidation defects in man. Pediat. Res. 23:387A. Bennett, M. J., Gray, R. G., Isherwood, D. M., Murphy, N., and Pollitt, R. J. (1985). The diagnosis and biochemical investigation of a patient with a short chain fatty acid oxidation defect. J. Inher. Metab. Dis. 8(Suppl. 2):135. Coates, P. M., Hale, D. E., Finocehiaro, G., Tanaka, K., and Winter, S. (1988). Genetic deficiency of short-chain aeyl-eoenzyme A dehydrogenase in cultured fibroblasts from a patient with muscle carnitine deficiency and severe skeletal muscle weakness. J. Clin. Invest. 81:171. Cohn, R. M., Updegrove, S., Yandrasitz, J. R., et al. (1978). Evaluation of continuous solvent extraction of organic acids from biological fluids. Clin. Biochem. 11:126. Green, D. E., Mii, S., Mahler, R., and Rock, R. M. (1954). Studies on the fatty acid oxidation system of animal tissues. III. Butyryl CoA dehydrogenase. J. Biol. Chem. 206:1. Gregersen, N., Kolvraa, S., and Mortensen, P. B. (1986). AcyI-CoA: Glyeine N-acyltransferase: In vitro studies on the glycine conjugation of straight and branched chained acyl-CoA esters in human liver. Bioehem. Med. Metabol. Biol. 35:210. Hawk, P. B., Oser, B. L., and Summerson, W. H. (1954). Practical Physiological Chemistry, 13th ed., Blakiston, New York. Holmes, R. S., Dnley, J. A., and Hilgers, J. (1982). Sorbitol dehydrogenase genetics in the mouse: A "null" mutant in a "European" C57BL strain. Animal Blood Groups Biochem. Geneti. 13:263. Hyashi, M., Nakajima, Y., and Fisherman, W. H. (1964). The cytologic demonstration of B-glueuronidase employing naphthol AS-B1 glueuronide and hexazonium; A preliminary report. J. Histochem. Cytochem. 12:293. Jezyk, P. F. (1979). Screening for inborn errors of metabolism in dogs and cats. In Hommes, F. A. (ed.), Models for the Study o f Inborn Errors o f Metabolism, Elsevier/North-Holland, Amsterdam. Jezyk, P. F. (1983). Metabolic diseases--an emerging area of veterinary pediatrics. Compen. Contin. Edue. 5:1026. Kolvraa, S., and Gregersen, N. (1986). Acyl-CoA: glycine N-acyltransferase: Organelle localization and affinity toward straight and branched chained aeyl-CoA esters in rat liver. Bioehem. Ivied. Metabol. Biol. 37:98. Kolvraa, S., Gregersen, N., and Brandt, N. J. (1980). Excretion of short chain N-acylglycines in the urine of a patient with D-glyceric acidemia. Clin. Chim. Aeta 106:215. Lalley, P. A., and Shows, T. B. (1974). Lysosomal and microsomal glucuronidase: Genetic variant alters electrophoretic mobility of both hydrolases. Science 185:442. Lee, C. Y., Lee, S. M., Lewis, S., and Johnson, F. M. (1980). Identification and biochemical analysis of mouse mutants deficient in cytoplasmic malic enzyme. Biochemistry 19:5098. Lyon, M. F. (1987). Mouse chromosome atlas. Mouse News Lett. 78:12. Potter, M. (1985). History of the BALB/c family. In Potter, M. (ed.), The BALB/c Mouse Genetics and Immunology, Springer-Verlag, Berlin, Vol. 122, pp. 1-5. Prochazka, M., and Leiter, E. H. (1986). A null activity variant found at the butyryl CoA dehydrogenase (Bcd-1) locus in BALB/cByJ subline. Mouse News Letter. 75:31. Prochazka, M., Kozak, U. C., and Kozak, L. P, (1988). A glyeerol-3-phosphate dehydrogenase null mutant in BALB/cHeA mice J. Biol. Chem. (in press). Seeley, T. A., and Holmes, R. S. (1981 ). Genetics and ontogeny of butyryl CoA dehydrogenase in the mouse and linkage of Bed-1 with Dao-1. Biochem. Gene. 19:333. Sul, H. S., Wise, S. L., Brown, M. L., and Rubin, C. S. (1984). Cloning of eDNA sequences for murine malic enzyme and the identification of aberrantly large malic enzyme mRNA in MOD-1 null mice. J. Biol. Chem. 259:555. Tanaka, K., Hine, D. G., West-Dull, A., et al. (1980). Gas chromatographic method of evaluation for urinary organic acids. 1. Retention indices of 155 metabolically important compounds. Clin. Chem. 26:1839. Turnbull, D. M., Bartlett, K., Stevens, D. L., Alberti, K. G., Gibson, G. J., Johnson, M. A., McCulloch, A. J., and Sherratt, H. S. (1984). Short chain acyl-CoA dehydrogenase deficiency associated with a lipid-storage myopathy and secondary carnitine deficiency. N. Engl. J. Med. 311:1232.

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