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IVD
isovaleryl-CoA dehydrogenase
The IVD gene provides instructions for an enzyme essential in the metabolic pathway that breaks down the amino acid leucine, helping to prevent the accumulation of harmful byproducts. The IVD gene encodes the isovaleryl-CoA dehydrogenase enzyme, which is crucial for the body's ability to process dietary proteins.
IVD is located on the long (q) arm of chromosome 15, at band 15q15.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The IVD gene provides the genetic blueprint for isovaleryl-CoA dehydrogenase, an enzyme vital for normal metabolic function. This enzyme is located within mitochondria, the cellular components responsible for converting food into usable energy. It specifically participates in the breakdown of the amino acid leucine, a building block of proteins.
Proper functioning of the IVD gene is critical because defects can lead to the impaired processing of leucine, causing a build-up of potentially toxic substances in the body. This can result in conditions such as isovaleric acidaemia, an inherited metabolic disorder.
What the gene does
The isovaleryl-CoA dehydrogenase enzyme, produced from the IVD gene, is an important component of the metabolic machinery that processes proteins. Dietary proteins are broken down into amino acids, which are then further metabolised to provide energy for cellular growth and development. This enzyme specifically facilitates a key step in the catabolism of leucine, one of the essential amino acids.
Inside the mitochondria, isovaleryl-CoA dehydrogenase catalyses the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA. This chemical reaction is the third stage in the overall pathway for leucine breakdown. Subsequent reactions further transform 3-methylcrotonyl-CoA into compounds that can enter the energy production cycle. When the IVD gene is not functioning correctly, this metabolic step is impaired, leading to an accumulation of isovaleryl-CoA and related compounds.
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Chromosome location
The IVD gene is situated on chromosome 15 at position 15q15.1. This specifies its precise location on the long arm (q) of chromosome 15, within region 15, band 1. This genomic address helps in understanding its position relative to other genes and its role in human genetic mapping.
Protein structure
The IVD gene directs the synthesis of a protein consisting of 426 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variations within the IVD gene can affect the function of the isovaleryl-CoA dehydrogenase enzyme. These variations, also known as mutations or pathogenic variants, can alter the enzyme's structure or reduce its production. Such changes may lead to a diminished ability to process leucine effectively.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1186G>C | p.Asp396His | Pathogenic/Likely pathogenic | ★★☆☆ | Isovaleryl-CoA dehydrogenase deficiency |
c.1201G>T | p.Glu401Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Isovaleryl-CoA dehydrogenase deficiency |
c.144+1G>C | - | Pathogenic | ★★☆☆ | Isovaleryl-CoA dehydrogenase deficiency |
c.163A>T | p.Lys55Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Isovaleryl-CoA dehydrogenase deficiency |
c.506_507insT | p.Gly170fs | Pathogenic/Likely pathogenic | ★★☆☆ | Isovaleryl-CoA dehydrogenase deficiency |
c.585G>A | p.Trp195Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Isovaleryl-CoA dehydrogenase deficiency |
c.631A>G | p.Thr211Ala | Pathogenic/Likely pathogenic | ★★☆☆ | Isovaleryl-CoA dehydrogenase deficiency |
c.667dup | p.Thr223fs | Pathogenic/Likely pathogenic | ★★☆☆ | Isovaleryl-CoA dehydrogenase deficiency |
c.782del | p.Pro261fs | Pathogenic/Likely pathogenic | ★★☆☆ | Isovaleryl-CoA dehydrogenase deficiency |
c.879-2A>G | - | Pathogenic | ★★☆☆ | Isovaleryl-CoA dehydrogenase deficiency |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the IVD gene are primarily associated with isovaleric acidaemia. This condition is an autosomal recessive inherited metabolic disorder characterised by the body's inability to properly break down leucine. The impaired enzyme function leads to the accumulation of harmful byproducts.
Inheritance pattern
Conditions caused by pathogenic IVD variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The IVD gene is included in several panels within the UK's NHS Genomic Medicine Service, indicating its clinical relevance. It is listed as 'green' in PanelApp for conditions such as Isovaleric acidaemia - Diagnostic (R450), Hyperammonaemia, Intellectual disability, and Likely inborn error of metabolism (R98), among others. A 'green' status signifies strong evidence for the gene's association with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the IVD gene?
The IVD gene provides instructions for creating the isovaleryl-CoA dehydrogenase enzyme, which is crucial for metabolising the amino acid leucine. This enzyme helps convert leucine into molecules the body can use for energy.
What happens if the IVD gene does not function correctly?
If the IVD gene does not function correctly, the body cannot properly break down leucine. This leads to an accumulation of toxic byproducts, which can cause metabolic disorders like isovaleric acidaemia.
How is isovaleric acidaemia inherited?
Isovaleric acidaemia is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of a pathogenic variant in the IVD gene, one from each parent, to develop the condition.
References
- Ensenauer R, Fingerhut R, Maier EM. Newborn screening for isovaleric acidemia using tandem mass spectrometry: data from 1.6 million newborns. Clinical chemistry. 2011. PMID: 21335445
- Lin WD, Wang CH, Lee CC. Genetic mutation profile of isovaleric acidemia patients in Taiwan. Molecular genetics and metabolism. 2007. PMID: 17027310
- Vockley J, Ensenauer R. Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity. American journal of medical genetics. Part C, Seminars in medical genetics. 2006. PMID: 16602101
- Ensenauer R, Vockley J, Willard JM. A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening. American journal of human genetics. 2004. PMID: 15486829
- Vockley J, Rogan PK, Anderson BD. Exon skipping in IVD RNA processing in isovaleric acidemia caused by point mutations in the coding region of the IVD gene. American journal of human genetics. 2000. PMID: 10677295
- Mohsen AW, Anderson BD, Volchenboum SL. Characterization of molecular defects in isovaleryl-CoA dehydrogenase in patients with isovaleric acidemia. Biochemistry. 1998. PMID: 9665741