HGNC Approved Gene Symbol: IVD
SNOMEDCT: 87827003; ICD10CM: E71.110;
Cytogenetic location: 15q15.1 Genomic coordinates (GRCh38): 15:40,405,795-40,435,947 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q15.1 | Isovaleric acidemia | 243500 | Autosomal recessive | 3 |
Isovaleryl-CoA dehydrogenase (EC 1.3.99.10) is a member of the acyl-CoA dehydrogenase family and is involved in the catabolism of leucine.
Matsubara et al. (1990) isolated 5 overlapping IVD cDNA clones from a human placenta cDNA library. The deduced 423-amino acid protein shares 35.8% and 31.6% sequence identity with human short and medium chain acyl-CoA dehydrogenases (606885, 607008), respectively, and 89.6% sequence identity with rat IVD. The leader sequence was determined to be overall positively charged, as is typical of other nuclear-encoded mitochondrial matrix enzymes. The molecular mass of the mature protein is 43 kD.
By Northern blot analysis of normal human liver and fibroblast poly(A)+ RNA, Matsubara et al. (1990) found 3 mRNA species of sizes 4.6, 3.8, and 2.1 kb hybridized to IVD cDNA. The 2.1-kb mRNA matched the size of cDNA and was considered to be the translatable species.
Parimoo and Tanaka (1993) determined that the IVD gene contains 12 exons and has a high GC content upstream of the initiation codon.
Kraus et al. (1987) used a rat cDNA for IVD in Southern blot analysis of DNAs from human-rodent somatic cell hybrids and in in situ hybridization for localization of the IVD gene to 15q13-q15.
In 5 fibroblast lines of different genotypes from patients with isovaleric acidemia (243500), Matsubara et al. (1990) found 3 mRNA species of similar sizes to normal mRNAs, suggesting that these variants are due in each case to a point mutation or a small deletion.
Vockley et al. (1991) identified 6 classes of patients with IVD deficiency. In size, IVD precursor and mature proteins produced by class I mutants are indistinguishable from their normal counterparts. Class II, III, and IV mutants make IVD precursor proteins 42 kD in size rather than the normal 45 kD. Subsequent processing in class III and IV mutants is normal but proceeds inefficiently in class II mutants. Class V mutants make no detectable IVD protein. Two different missense mutations were identified in class I mutants (607036.0001; 607036.0002). In cDNA from a class III mutant, a single base deletion at position 1179 (607036.0003) of the coding region was identified that led to a frameshift, predicting the incorporation of 8 abnormal amino acids followed by a premature termination codon. Sequencing of amplified IVD cDNA from a type V mutant failed to identify any abnormality; the defect might have involved translation of IVD mRNA. Vockley et al. (1991) identified a transcriptionally defective class of IVD mutant allele (type VI).
D'Annibale et al. (2021) generated an IVD null HEK293T cell line and transfected the cells with vectors containing IVD cDNA with mutations identified in patients with positive newborn screening for IVA. IVD with an R50P, M329T, R337Q, or c.1179del394 mutation resulted in reduced IVD protein content and activity. IVD with an A311V, T236I, or R411Q mutation resulted in stable IVD protein but no enzyme activity. IVD with a V174G mutation resulted in normal IVD content and activity.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human IVD is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a patient with type I isovaleric acidemia (243500), Vockley et al. (1991) demonstrated a change of thymine-125 to cytosine, which was predicted to cause a substitution of proline for leucine at position 13 of the mature IVD protein.
In a patient with type I IVD deficiency (243500), Vockley et al. (1991) found a change of cytosine-596 to adenine, predicting a substitution of valine for glycine at position 170 of the mature protein.
In a patient with type III isovaleric acidemia (243500), Vockley et al. (1991) found deletion of 1 of a triplet of T residues at positions 1177 to 1179. This led to a frameshift that predicted the incorporation of 8 abnormal amino acids followed by a premature termination codon.
In cDNA from a patient with type II IVD deficiency (243500), Vockley et al. (1992) identified a 90-bp deletion encompassing bases 145 to 234. The deletion was caused by an error in RNA splicing and predicted an in-frame deletion of 30 amino acids beginning with leucine-20 of the mature IVD protein.
In fibroblasts from a patient with isovaleric acidemia (243500), Vockley et al. (2000) identified a 15-bp insertion at the 3-prime end of intron 7 of the IVD gene. This missplicing resulted from a G-to-A mutation in the intron 7 acceptor site, altering the AG acceptor to AA. Consequently, a cryptic splice acceptor site in intron 7, located 15 nucleotides upstream of exon 8, was used, accounting for the 15-nucleotide insertion in the cDNA. This insertion maintained the correct reading frame.
In fibroblasts from a patient with isovaleric acidemia (243500) and skipping of exon 2 of the IVD gene, Vockley et al. (2000) identified a C-to-T transition at nucleotide 148, resulting in an arg21-to-cys substitution. This mutation involved the same codon mutated in another patient but with a different nucleotide involved. The authors noted that these missense mutations strengthened preexisting cryptic splice acceptors adjacent to the natural splice junctions and apparently interfered with exon recognition, resulting in exon skipping.
By molecular genetic analysis of the IVD gene in 19 subjects in whom isovaleric acidemia (243500) was diagnosed through newborn screening by tandem mass spectrometry, Ensenauer et al. (2004) found that 47% of mutant alleles carried a recurrent mutation, 932C-T (ala282 to val; A282V). Surprisingly, family studies identified 6 healthy older sibs with identical genotype and biochemical evidence of IVA. The findings indicated the frequent occurrence of a novel mild and potentially asymptomatic phenotype of IVA, which has significant consequences for patient management and counseling.
D'Annibale, O. M., Koppes, E. A., Alodaib, A. N., Kochersperger, C., Karunanidhi, A., Mohsen, A.-W., Vockley, J. Characterization of variants of uncertain significance in isovaleryl-CoA dehydrogenase identified through newborn screening: an approach for faster analysis. Molec. Genet. Metab. 134: 29-36, 2021. [PubMed: 34535384] [Full Text: https://doi.org/10.1016/j.ymgme.2021.08.012]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Ensenauer, R., Vockley, J., Willard, J.-M., Huey, J. C., Sass, J. O., Edland, S. D., Burton, B. K., Berry, S. A., Santer, R., Grunert, S., Koch, H.-G., Marquardt, I., Rinaldo, P., Hahn, S., Matern, D. A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening. Am. J. Hum. Genet. 75: 1136-1142, 2004. [PubMed: 15486829] [Full Text: https://doi.org/10.1086/426318]
Kraus, J. P., Matsubara, Y., Barton, D., Yang-Feng, T. L., Glassberg, R., Ito, M., Ikeda, Y., Mole, J., Francke, U., Tanaka, K. Isolation of cDNA clones coding for rat isovaleryl-CoA dehydrogenase and assignment of the gene to human chromosome 15. Genomics 1: 264-269, 1987. [PubMed: 3446585] [Full Text: https://doi.org/10.1016/0888-7543(87)90053-x]
Matsubara, Y., Ito, M., Glassberg, R., Satyabhama, S., Ikeda, Y., Tanaka, K. Nucleotide sequence of messenger RNA encoding human isovaleryl-coenzyme A dehydrogenase and its expression in isovaleric acidemia fibroblasts. J. Clin. Invest. 85: 1058-1064, 1990. [PubMed: 2318964] [Full Text: https://doi.org/10.1172/JCI114536]
Parimoo, B., Tanaka, K. Structural organization of the human isovaleryl-CoA dehydrogenase gene. Genomics 15: 582-590, 1993. [PubMed: 8468053] [Full Text: https://doi.org/10.1006/geno.1993.1111]
Vockley, J., Matsubara, Y., Ikeda, Y., Tanaka, K. Identification of molecular defects responsible for isovaleric acidemia. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A227 only, 1989.
Vockley, J., Nagao, M., Parimoo, B., Tanaka, K. The variant human isovaleryl-CoA dehydrogenase gene responsible for type II isovaleric acidemia determines an RNA splicing error, leading to the deletion of the entire second coding exon and the production of a truncated precursor protein that interacts poorly with mitochondrial import receptors. J. Biol. Chem. 267: 2494-2501, 1992. [PubMed: 1310317]
Vockley, J., Parimoo, B., Tanaka, K. Molecular characterization of four different classes of mutations in the isovaleryl-CoA dehydrogenase gene responsible for isovaleric acidemia. Am. J. Hum. Genet. 49: 147-157, 1991. [PubMed: 2063866]
Vockley, J., Rogan, P. K., Anderson, B. D., Willard, J., Seelan, R. S., Smith, D. I., Liu, W. Exon skipping in IVD RNA processing in isovaleric acidemia caused by point mutations in the coding region of the IVD gene. Am. J. Hum. Genet. 66: 356-367, 2000. [PubMed: 10677295] [Full Text: https://doi.org/10.1086/302751]