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ALDH7A1
aldehyde dehydrogenase 7 family member A1
The ALDH7A1 gene provides instructions for an enzyme called antiquitin, which plays a crucial role in the breakdown of the amino acid lysine within the brain. ALDH7A1 is a member of the aldehyde dehydrogenase gene family, producing an enzyme essential for cellular metabolism.
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, also known as aldehyde dehydrogenase 7 family member A1, is part of a larger family of genes that encode enzymes responsible for processing aldehydes. It specifically provides the blueprint for producing an enzyme named antiquitin, or alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase.
Antiquitin is vital for maintaining normal brain function, primarily through its involvement in metabolic pathways. Dysregulation of this gene's activity can lead to significant health concerns, particularly neurological conditions.
What the gene does
The ALDH7A1 gene encodes the antiquitin enzyme, which is critical for the normal metabolism of lysine, an essential amino acid. Within the cells, antiquitin is typically found in the cytosol, the fluid component of the cytoplasm, and also within the cell's nucleus. Its primary metabolic role involves a specific step in the lysine degradation pathway.
Antiquitin facilitates the conversion of alpha-aminoadipic semialdehyde to alpha-aminoadipate. This enzymatic reaction is a key component of the biochemical cascade that breaks down lysine into other molecules, which are then used for energy production and to synthesise other essential compounds in the brain. Proper functioning of this enzyme is therefore crucial for cellular energy homeostasis and the production of necessary biomolecules.
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Chromosome location
The ALDH7A1 gene is located on chromosome 5, specifically at position 5q23.2. This genomic address specifies its precise location on the long (q) arm of chromosome 5. The gene provides the instructions for a protein that is 539 amino acids long.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the ALDH7A1 gene can affect the production or function of the antiquitin enzyme, leading to impaired lysine metabolism. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions within the gene sequence. The impact of a specific variant depends on its location and how it alters the enzyme's structure and activity.
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.200del | p.Thr67fs | 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 |
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 ALDH7A1 gene are the underlying cause of pyridoxine-dependent epilepsy, an inherited metabolic disorder. This condition is characterised by seizures that typically begin in infancy and are often resistant to standard anti-epileptic medications but respond to treatment with pyridoxine (vitamin B6). The inheritance pattern for conditions associated with ALDH7A1 is autosomal recessive.
- 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 National Health Service (NHS) Genomic Medicine Service. It is listed on several NHS Genomic Test Directory panels, including those for DDG2P, Early onset or syndromic epilepsy, Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders.
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. This enzyme is essential for a specific step in the breakdown of the amino acid lysine within cells, particularly in the brain.
What health condition is associated with variants in the ALDH7A1 gene?
Variants in the ALDH7A1 gene are associated with pyridoxine-dependent epilepsy. This is a condition characterised by seizures that often respond to treatment with pyridoxine (vitamin B6).
How is pyridoxine-dependent epilepsy inherited?
Pyridoxine-dependent epilepsy associated with ALDH7A1 variants is inherited in an autosomal recessive manner. This means an individual must inherit two altered copies of the 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