Characterization of Molecular Defects in Isovaleryl-CoA Dehydrogenase in Patients with Isovaleric Acidemia

Mohsen, Al‐Walid; Anderson, Bambi D.; Volchenboum, Samuel L.; Battaile, Kevin P.; Tiffany, Karen; Roberts, David L.; Kim, Jung‐Ja P.; Vockley, Jerry

doi:10.1021/bi973096r

Cited by 61 publications

(76 citation statements)

References 30 publications

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“…Several direct and indirect methods to assay IVD activity have been published and, in addition to molecular genetic analysis, can be used to confirm a diagnosis of IVA [Hyman and Tanaka, 1986;Mohsen et al, 1998;Rhead and Tanaka, 1980;Shih et al, 1973;Tajima et al, 2005;Vockley et al, 1991;Yoshida et al, 1985]. Fibroblasts, lymphocytes, and amniocytes all have measurable amounts of IVD activity and serve as ready sources of tissue for this purpose [Ensenauer et al, 2004;Kleij et al, 1995;Mohsen et al, 1998;Vockley et al, 1991].…”

Section: Biochemical Diagonosis and Follow Upmentioning

confidence: 99%

“…Fibroblasts, lymphocytes, and amniocytes all have measurable amounts of IVD activity and serve as ready sources of tissue for this purpose [Ensenauer et al, 2004;Kleij et al, 1995;Mohsen et al, 1998;Vockley et al, 1991]. While significant residual activity blunts the level of abnormal metabolites, correlation between clinical presentation and enzyme activity has been poor [Hyman and Tanaka, 1986;Ikeda et al, 1985b;Vockley et al, 1991].…”

Section: Biochemical Diagonosis and Follow Upmentioning

confidence: 99%

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Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Vockley

Ensenauer

2006

American J of Med Genetics Pt C

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196

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Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of derivatives of isovaleryl-CoA. It was the first organic acidemia recognized in humans and can cause significant morbidity and mortality. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individuals. Both intra-and inter-familial variability have been recognized. Initially, two phenotypes with either an acute neonatal or a chronic intermittent presentation were described. More recently, a third group of individuals with mild biochemical abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Human IVD has been purified from tissue and recombinant sources and its biochemical and physical properties have been extensively studied. Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. This mutation leads to a partially active enzyme with altered catalytic properties; however, its effects on clinical outcome and the necessity of therapy are still unknown. A better understanding of the heterogeneity of this disease and the relevance of genotype/phenotype correlations to clinical management of patients are among the challenges remaining in the study of this disorder in the coming years.

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Section: Biochemical Diagonosis and Follow Upmentioning

confidence: 99%

Section: Biochemical Diagonosis and Follow Upmentioning

confidence: 99%

Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Vockley

Ensenauer

2006

American J of Med Genetics Pt C

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196

161

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“…This partially purified enzyme sample showed maximum activity with isovaleryl-CoA as substrate (300 milliunits/mg of protein). (11,16). The higher S.E.…”

Section: Resultsmentioning

confidence: 99%

Cloning of a Gene for an Acyl-CoA Dehydrogenase from Pisum sativum L. and Purification and Characterization of Its Product as an Isovaleryl-CoA Dehydrogenase

Reinard¹,

Janke²,

Willard³

et al. 2000

Journal of Biological Chemistry

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Isovaleryl-CoA dehydrogenase (IVD, EC 1.3.99.10) catalyzes the third step in the catabolism of leucine in mammals. Deficiency of this enzyme leads to the clinical disorder isovaleric acidemia. IVD has been purified and characterized from human and rat liver, and the x-ray crystallographic structure of purified recombinant human IVD has been reported. Nothing is known about IVD activity in plants, although cDNA clones from Arabidopsis thaliana and partial sequences from Gossypium hirsutum and Oryza sativa have been identified as putative IVDs based on sequence homology and immuno cross-reactivity. In this report we describe the identification and characterization of an IVD from pea, purification of the enzyme using a novel and rapid auxin affinity chromatography matrix, and cloning of the corresponding gene. At the amino acid level, pea IVD is 60% similar to human and rat IVD. The specific activity and abundance of plant IVD was found to be significantly lower than for its human counterpart and exhibits developmental regulation. Substrate specificity of the plant enzyme is similar to the human IVD, and it crossreacts to anti-human IVD antibodies. Molecular modeling of the pea enzyme based on the structure of human IVD indicates a high degree of structural similarity among these enzymes. Glu-244, shown to function as the catalytic base in human IVD along with most of the amino acids that make up the acyl CoA binding pocket, is conserved in pea IVD. The genomic structure of the plant IVD gene consists of 13 exons and 12 introns, spanning approximately 4 kilobases, and the predicted RNA splicing sites exhibit the extended consensus sequence described for other plant genes.

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“…More than 60 disease-causing mutations in the IVD gene have been described. The majority are point mutations, but splice site mutations, nonsense mutations, missense mutations, deletions, and insertions have also been described [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33].…”

Section: Argentinamentioning

confidence: 99%

Aspects of Newborn Screening in Isovaleric Acidemia

Schlune

Riederer

Mayatepek

et al. 2018

IJNS

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Isovaleric acidemia (IVA), an inborn error of leucine catabolism, is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene, resulting in the accumulation of derivatives of isovaleryl-CoA including isovaleryl (C5)-carnitine, the marker metabolite used for newborn screening (NBS). The inclusion of IVA in NBS programs in many countries has broadened knowledge of the variability of the condition, whereas prior to NBS, two distinct clinical phenotypes were known, an "acute neonatal" and a "chronic intermittent" form. An additional biochemically mild and potentially asymptomatic form of IVA and its association with a common missense mutation, c.932C>T (p.A282V), was discovered in subjects identified through NBS. Deficiency of short/branched chain specific acyl-CoA dehydrogenase (2-methylbutyryl-CoA dehydrogenase), a defect of isoleucine degradation whose clinical significance remains unclear, also results in elevated C5-carnitine, and may therefore be detected by NBS for IVA. Treatment strategies for the long-term management of symptomatic IVA comprise the prevention of catabolism, dietary restriction of natural protein or leucine intake, and supplementation with L-carnitine and/or L-glycine. Recommendations on how to counsel and manage individuals with the mild phenotype detected by NBS are required.

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Characterization of Molecular Defects in Isovaleryl-CoA Dehydrogenase in Patients with Isovaleric Acidemia

Cited by 61 publications

References 30 publications

Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Cloning of a Gene for an Acyl-CoA Dehydrogenase from Pisum sativum L. and Purification and Characterization of Its Product as an Isovaleryl-CoA Dehydrogenase

Aspects of Newborn Screening in Isovaleric Acidemia

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