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ALDH4A1
aldehyde dehydrogenase 4 family member A1
The ALDH4A1 gene provides instructions for an enzyme called pyrroline-5-carboxylate dehydrogenase, which plays a crucial role in the breakdown of the amino acid proline within the body's cells. The ALDH4A1 gene encodes the pyrroline-5-carboxylate dehydrogenase enzyme, primarily located in mitochondria.
ALDH4A1 is located on the short (p) arm of chromosome 1, at band 1p36.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The ALDH4A1 gene, also known as aldehyde dehydrogenase 4 family member A1, is integral to human metabolism. It directs the production of pyrroline-5-carboxylate dehydrogenase, an enzyme found in various tissues throughout the body. This enzyme is particularly active within the mitochondria, the cell's powerhouses, where it participates in energy production pathways. Understanding ALDH4A1's role is key to comprehending certain metabolic conditions.
What the gene does
The primary function of the ALDH4A1 gene product, pyrroline-5-carboxylate dehydrogenase, is to facilitate a crucial step in amino acid metabolism. Specifically, it initiates the second stage of proline breakdown. In this process, the enzyme converts pyrroline-5-carboxylate, an intermediate product from the initial step of proline catabolism, into the amino acid glutamate. The conversion between proline and glutamate, mediated by various enzymes, is vital for maintaining an adequate supply of amino acids necessary for protein synthesis and for efficient energy transfer within cells. Dysfunction of this enzyme can disrupt the balance of these metabolic pathways.
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Chromosome location
The ALDH4A1 gene is situated on the short arm of chromosome 1, at position 1p36.13. This specific genomic location provides the gene's address within the human genome, indicating where the instructions for pyrroline-5-carboxylate dehydrogenase are stored. The precise placement helps in understanding potential genetic linkages and inherited patterns.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The ALDH4A1 gene encodes a protein composed of 563 amino acid residues, consistent with its function as a metabolic enzyme.
Key variants
Variants within the ALDH4A1 gene can alter the normal function of the pyrroline-5-carboxylate dehydrogenase enzyme. These genetic changes can range from small alterations in the DNA sequence to larger structural rearrangements. Such variants may lead to a reduction or complete loss of enzyme activity, thereby impacting metabolic pathways where the enzyme is involved.
Sample of pathogenic variants
8 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.139C>T | p.Arg47Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperprolinemia type 2 |
c.1560dup | p.Gly521fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperprolinemia type 2 |
c.866+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperprolinemia type 2 |
g.(?_19199339)_(19201095_?)del | - | Pathogenic | ★☆☆☆ | Hyperprolinemia type 2 |
c.200del | p.Val67fs | Pathogenic | ★☆☆☆ | Hyperprolinemia type 2 |
c.451C>T | p.Gln151Ter | Pathogenic | ★☆☆☆ | Hyperprolinemia type 2 |
c.72del | p.Arg23_Trp24insTer | Pathogenic | ★☆☆☆ | Hyperprolinemia type 2 |
c.960_964del | p.His321fs | Pathogenic | ★☆☆☆ | Hyperprolinemia type 2 |
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
Variants in the ALDH4A1 gene are primarily associated with hyperprolinemia type II. This condition is characterised by an excessive accumulation of proline in the blood, which results from the impaired breakdown of proline due to reduced or absent function of the pyrroline-5-carboxylate dehydrogenase enzyme. Hyperprolinemia type II is generally considered the more severe form of hyperprolinemia and can manifest with neurological issues, such as seizures or intellectual disability.
No disease links recorded for this gene in our reference set.
UK clinical status
In the UK, the ALDH4A1 gene is present on several NHS Genomic Medicine Service (GMS) approved panels. These include the DDG2P panel, the Intellectual disability panel, the Likely inborn error of metabolism panel (R98), and the Undiagnosed metabolic disorders panel, all listed as 'green' indicating genes with strong evidence for association with disease.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the ALDH4A1 gene?
The ALDH4A1 gene provides instructions for creating pyrroline-5-carboxylate dehydrogenase, an enzyme crucial for breaking down the amino acid proline into glutamate within the mitochondria of cells. This process is essential for amino acid balance and cellular energy.
What condition is associated with ALDH4A1 gene variants?
Variants in the ALDH4A1 gene are linked to hyperprolinemia type II, a metabolic disorder characterised by an excess of proline in the blood. This can lead to neurological symptoms like seizures and intellectual disability.
Where is the ALDH4A1 gene located?
The ALDH4A1 gene is located on chromosome 1, specifically at position 1p36.13. This genomic location helps in identifying and studying the gene's role in health and disease.
References
- Inagaki E, Ohshima N, Takahashi H. Crystal structure of Thermus thermophilus Delta1-pyrroline-5-carboxylate dehydrogenase. Journal of molecular biology. 2006. PMID: 16934832
- Sophos NA, Vasiliou V. Aldehyde dehydrogenase gene superfamily: the 2002 update. Chemico-biological interactions. 2003. PMID: 12604184
- Vasiliou V, Pappa A. Polymorphisms of human aldehyde dehydrogenases. Consequences for drug metabolism and disease. Pharmacology. 2000. PMID: 10971205
- Vasiliou V, Bairoch A, Tipton KF. Eukaryotic aldehyde dehydrogenase (ALDH) genes: human polymorphisms, and recommended nomenclature based on divergent evolution and chromosomal mapping. Pharmacogenetics. 1999. PMID: 10780262
- Yoshida A, Rzhetsky A, Hsu LC. Human aldehyde dehydrogenase gene family. European journal of biochemistry. 1998. PMID: 9490025
- Geraghty MT, Vaughn D, Nicholson AJ. Mutations in the Delta1-pyrroline 5-carboxylate dehydrogenase gene cause type II hyperprolinemia. Human molecular genetics. 1998. PMID: 9700195
- Hu CA, Lin WW, Valle D. Cloning, characterization, and expression of cDNAs encoding human delta 1-pyrroline-5-carboxylate dehydrogenase. The Journal of biological chemistry. 1996. PMID: 8621661