Complementation studies of isovaleric acidemia and glutaric aciduria type II using cultured skin fibroblasts.

Dubiel, Barbara; Dabrowski, Christine; Wetts, Richard; Tanaka, Kay

doi:10.1172/jci111113

Cited by 18 publications

(8 citation statements)

References 28 publications

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“…IVDHase activity was found to be uniformly low, regardless of the clinical phenotype (11). We then did genetic complementation studies using polyethylene glycol-induced heterokaryons but failed to demonstrate the existence of genetic heterogeneity (12). However, these results did not exclude the possibility that more than one mutant allele exists, each encoding for a varient IVDHase that is equally deficient in activity.…”

mentioning

confidence: 98%

Molecular heterogeneity of variant isovaleryl-CoA dehydrogenase from cultured isovaleric acidemia fibroblasts.

Ikeda¹,

Keese²,

Tanaka³

1985

Proc. Natl. Acad. Sci. U.S.A.

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confidence: 98%

Molecular heterogeneity of variant isovaleryl-CoA dehydrogenase from cultured isovaleric acidemia fibroblasts.

Ikeda¹,

Keese²,

Tanaka³

1985

Proc. Natl. Acad. Sci. U.S.A.

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“…In the previous study of 12 IVA cell lines using polyethylene glycol-induced heterokaryons, no complementation groups were found (14), indicating the involvement of a single IVD gene in this disease. However, the analysis of variant IVD in 15 IVA fibroblast cell lines using [35S]methionine labeling, immunoprecipitation, and SDS-PAGE revealed five distinct classes of variants (10).…”

Section: Introductionmentioning

confidence: 64%

Nucleotide sequence of messenger RNA encoding human isovaleryl-coenzyme A dehydrogenase and its expression in isovaleric acidemia fibroblasts.

Matsubara¹,

M²,

Glassberg³

et al. 1990

J. Clin. Invest.

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Isovaleric acidemia (IVA) is caused by a genetic deficiency of isovaleryl-CoA dehydrogenase (IVD). At least five distinct variant IVD alleles are known. We isolated five overlapping IVD cDNA clones from a human placenta cDNA library. They covered the entire coding region, except the initiation codon, and 587 bp in the 3'-noncoding region plus the poly(A) tail. The structure of the initiation site was identified by the study of genomic DNA and by the sequence comparison with rat IVD. Human IVD shared 89.6, 35.8, and 31.6% identical amino acid residues with rat IVD and human short and medium chain acyl-CoA dehydrogenases, respectively. In the Northern blot analysis of normal human liver and fibroblast poly(A)+ RNA, three mRNA species of different sizes (4.6, 3.8, and 2.1 kb) hybridized to IVD cDNA. Three mRNA species with similar sizes were also detected in five IVA fibroblast lines of different genotypes (variants 1, 1 X 2, 2, 3, and 5), suggesting that these variants are each due to a point mutation or small deletion. (J.

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“…The concentration of 3-hydroxyisovaleric acid observed in the control fluids (5.00 + 1.66~tmol/L) is closely comparable to that reported by Jakobs et al (1984) The results of HMG CoA lyase assays of cultured amniocytes confirmed the chemical diagnosis and this was further confirmed by the results of the isovalerate incorporation assay. In the latter assay, the test substrate is introduced at the start of the L-leucine metabolic pathway after ketoacid decarboxylation and thus is suitable for the diagnosis of any enzyme deficiency in the pathway up to entry into the tricarboxylic acid cycle, including isovaleric acidaemia, holocarboxylase synthetase deficiency, 3-methylcrotonylglycinuria and HMG CoA lyase deficiency, and also for multiple acyl CoA dehydrogenase deficiency (Chalmers and Spellacy, 1979;Dubiel et al, 1983;Sovik et al, 1984). The present work indicates the method is also suitable for the prenatal diagnosis of these conditions, offering the potential advantage of a single enzyme assay for the prenatal diagnosis of five different inherited metabolic disorders.…”

Section: Discussionmentioning

confidence: 99%

Prenatal diagnosis of 3‐Hydroxy‐3‐methylglutaric aciduria by GC‐MS and enzymology on cultured amniocytes and chorionic villi

Chalmers

Tracey

Mistry

et al. 1989

J of Inher Metab Disea

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, Middlesex. UK. 3-Hydrory-3-methylglutaric (HMO) aciduria is a disorder of L-leuc-ine metabolism and ketone body biosynthesis characteriaed by recurrent acute life-threatening episodes resembling Reye's syndrome. Prenatal diagnosis was requested by the parents of a child with this condition and was carried out by amniocenteeis at 16 weeks' gestation. Amniotic fluid concentrations (capillary GC and GC-HS) (Umole/L) were for W G 34.6 (N=1.21+0.38), 3-hydroryisovalerate (HIV) 33.9 (N=4.78f1.91). 3-methylglutaconate (3MAG) 31.7 (N=0.62-0.90) and 3-methylglutarate(3MG) 1.23 (N=0.12-0.26) consistent with an affected fetus. Termination was carried out on the basis of these data. The diagnosis was confirmed immediately by analysis of fetal plasma for organic acid6:concentra-tions of HMG, HIV, 3MAG and 3MG were 67.3, 36.9, 31.3 and 11.31lmoles/L respectively. Subsequent enzymology on cultured amoiocytes gave mean results for isovalerate incorporation into protein (pmol/h/mg protein) of 48 compared to simultaneous controls of 252; direct WIG CoA lyaS-3 activity (moles ilMG CoA removed/min/mg protein) was 0.05 compared to simultaneous controls of 9.16. Direct HMG CoA lyase measurements on chorionic villus tissue obtained at termination gave mean activities of 0.87 compared to controls of 8.04. These results provide the first prenatal diagnosis of HMG aciduria, demonstrate the rapid, accurate and unambiguous diagnosis at 16 weeks using direct GC-MS analysis of amniotic fluid and indicate the suitability of chorionic villus biopsy for future earlier (9 weeks) prenatal diagnoses of this condition. ORGANIC ACIDURIA IN PATIENTS WITH GLYCOGWOSIS TYPE I. Intrigued by the persistent growth retardation of some glucose-6-phosphatase-deficient patients, we investigated the urinary excretion of lactate, 2-oxoglutarate and citrate, reflecting organic acid overproduction , and glycerol reflecting impaired gluconeogenesis, in 17 patients with type I A and 1 patient with type IB glycogenosis. The urine was collected during 8-10 successive days twice daily. The mean lactate-creatinine ratio (mM/mM) ranged from 0.27 to 11.17 (normal 0.010 to0.058, N=36) in 5 patients with a height < P3. The lactate excretion in these patients varied considerably during successive days and less during gastric drip feeding at night. The mean lactate-creatinine ratio in the other patients was more constant and ranged from 0.04 to 0.34, The mean 2-oxoglutarate-creatinine ratio (mM/mM) ranged from 0.17 to 0.84 (normal 0 to 0.05, N=15) in 4 of 5 growth retarded patients. In the other patients it ranged from 0.01 to 0.43. The 2-oxoglutarate excretion per patient varied little. The mean citrate-creatinine ratio (mM/mM) ranged from 0.03 to 0.84 in all patients (normal 0.12 to 0.73, N=15). The mean glycerol-creatinine ratio (mM/mM) ranged from 0.01 to 0.11 (normal 0.005 to 0.03, n=15). We conclude that the lactate-creatinine ratio reflects both the adequacy of the dietary treatment and the severity of the disease, whereas the 2-oxoglutarate-creatinine ratio reflects...

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Complementation studies of isovaleric acidemia and glutaric aciduria type II using cultured skin fibroblasts.

Cited by 18 publications

References 28 publications

Molecular heterogeneity of variant isovaleryl-CoA dehydrogenase from cultured isovaleric acidemia fibroblasts.

Molecular heterogeneity of variant isovaleryl-CoA dehydrogenase from cultured isovaleric acidemia fibroblasts.

Nucleotide sequence of messenger RNA encoding human isovaleryl-coenzyme A dehydrogenase and its expression in isovaleric acidemia fibroblasts.

Prenatal diagnosis of 3‐Hydroxy‐3‐methylglutaric aciduria by GC‐MS and enzymology on cultured amniocytes and chorionic villi

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