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ALDH7A1
aldehyde dehydrogenase 7 family member A1
The ALDH7A1 gene encodes an enzyme crucial for breaking down the amino acid lysine, with genetic changes in this gene linked to pyridoxine-dependent epilepsy. The ALDH7A1 gene is part of the aldehyde dehydrogenase family, producing an enzyme known as antiquitin.
ALDH7A1 is located on the long (q) arm of chromosome 5, at band 5q23.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The ALDH7A1 gene, or aldehyde dehydrogenase 7 family member A1, is integral to cellular metabolism. It provides instructions for creating an enzyme called α-aminoadipic semialdehyde (α-AASA) dehydrogenase, also known as antiquitin. This enzyme is essential for the normal breakdown of the amino acid lysine within the body, particularly in the brain.
Dysfunction of the ALDH7A1 gene, typically due to inherited variants, is associated with specific neurological conditions, highlighting its importance in metabolic pathways.
What the gene does
The ALDH7A1 gene belongs to the aldehyde dehydrogenase (ALDH) gene family, which is responsible for producing enzymes that process aldehydes. Specifically, the ALDH7A1 gene instructs the cell to make antiquitin, an enzyme found in the cell's cytoplasm and nucleus. This enzyme is a critical component in the intricate pathway that breaks down lysine, an essential amino acid.
Antiquitin facilitates a key step in lysine catabolism: the conversion of α-aminoadipic semialdehyde to α-aminoadipate. This process is necessary for energy production and the creation of other vital molecules within the brain. Proper functioning of the ALDH7A1 enzyme ensures the efficient metabolism of lysine, preventing the accumulation of potentially toxic by-products.
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Chromosome location
The ALDH7A1 gene is located on chromosome 5, specifically at position 5q23.2. This genomic address pinpoints its exact site on the long arm of chromosome 5. As an autosomal gene, ALDH7A1 is present on one of the non-sex chromosomes, meaning it is inherited independently of sex.
Protein structure
The ALDH7A1 gene encodes a protein consisting of 539 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the ALDH7A1 gene can alter the function of the antiquitin enzyme. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions. Such alterations can impair the enzyme's ability to properly metabolise lysine, leading to the accumulation of harmful metabolic intermediates.
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.1171G>T | p.Glu391Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pyridoxine-dependent epilepsy |
c.1344T>A | p.Asn448Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Pyridoxine-dependent epilepsy |
c.1432T>A | p.Cys478Ser | Pathogenic | ★★☆☆ | Pyridoxine-dependent epilepsy |
c.1489+2T>C | - | Pathogenic | ★★☆☆ | Pyridoxine-dependent epilepsy |
c.1524dup | p.Gly509fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyridoxine-dependent epilepsy |
c.1553G>C | p.Arg518Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Pyridoxine-dependent epilepsy |
c.312+1G>T | - | Pathogenic | ★★☆☆ | Pyridoxine-dependent epilepsy |
c.442C>T | p.Gln148Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pyridoxine-dependent epilepsy |
c.605G>A | p.Gly202Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Pyridoxine-dependent epilepsy |
c.871+1G>A | - | Pathogenic | ★★☆☆ | Pyridoxine-dependent epilepsy |
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 ALDH7A1 gene are the primary cause of Pyridoxine-dependent epilepsy, an autosomal recessive neurological disorder. This condition is characterised by seizures that typically begin in infancy and are often resistant to standard antiepileptic drugs, but respond to treatment with pyridoxine (vitamin B6). The underlying mechanism involves impaired lysine metabolism, leading to a build-up of neurotoxic substances.
- Pyridoxine-dependent epilepsy Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ALDH7A1 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
ALDH7A1 is recognised in the UK by the NHS Genomic Medicine Service, appearing on several approved panels. It is listed as 'green' on DDG2P, Early onset or syndromic epilepsy, Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders panels.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ALDH7A1 gene?
The ALDH7A1 gene provides instructions for making an enzyme called antiquitin, which is crucial for the breakdown and metabolism of the amino acid lysine, particularly in the brain. This process is essential for energy production and creating other vital molecules.
What condition is primarily associated with ALDH7A1 gene variants?
Variants in the ALDH7A1 gene are primarily associated with Pyridoxine-dependent epilepsy. This is a rare, inherited neurological disorder characterised by seizures that typically respond to treatment with vitamin B6 (pyridoxine).
How is Pyridoxine-dependent epilepsy inherited?
Pyridoxine-dependent epilepsy is inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the ALDH7A1 gene, one from each parent, to develop the condition.
References
- Plecko B, Paul K, Paschke E. Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene. Human mutation. 2007. PMID: 17068770
- Bok LA, Struys E, Willemsen MA. Pyridoxine-dependent seizures in Dutch patients: diagnosis by elevated urinary alpha-aminoadipic semialdehyde levels. Archives of disease in childhood. 2007. PMID: 17088338
- Kanno J, Kure S, Narisawa A. Allelic and non-allelic heterogeneities in pyridoxine dependent seizures revealed by ALDH7A1 mutational analysis. Molecular genetics and metabolism. 2007. PMID: 17433748
- Pearl PL, Taylor JL, Trzcinski S. The pediatric neurotransmitter disorders. Journal of child neurology. 2007. PMID: 17690069
- Mills PB, Struys E, Jakobs C. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nature medicine. 2006. PMID: 16491085
- Fong WP, Cheng CH, Tang WK. Antiquitin, a relatively unexplored member in the superfamily of aldehyde dehydrogenases with diversified physiological functions. Cellular and molecular life sciences : CMLS. 2006. PMID: 17131062