Alternative titles; symbols
HGNC Approved Gene Symbol: ALDH7A1
SNOMEDCT: 734434007;
Cytogenetic location: 5q23.2 Genomic coordinates (GRCh38) : 5:126,541,841-126,595,219 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q23.2 | Epilepsy, early-onset, 4, vitamin B6-dependent | 266100 | Autosomal recessive | 3 |
The ALDH7A1 gene encodes an aldehyde dehydrogenase. Mills et al. (2006) determined that the protein is an alpha-aminoadipic semialdehyde dehydrogenase in the pipecolic acid pathway of lysine catabolism.
In screening a rat mucosa cDNA subtraction library, Lee et al. (1994) found a clone that exhibited a remarkable degree of homology with a previously described cDNA from the green garden pea, designated the 26g pea turgor protein. They obtained a partial cDNA from rat and a complete cDNA from human. The deduced human protein has a molecular mass of 55 kD and was designated antiquitin (ATQ1) because of its remarkable level of conservation through evolution. Human antiquitin is 60% homologous to the green pea 26g. Analysis of mRNA indicated that the largest amounts were found in rat kidney and liver and in cultured human hepatoma cells. Only minimal amounts were detected in human peripheral blood leukocytes, rat lung, or cultured human fibroblasts. Attempts to induce the mRNA by heat-shock, dehydration, ionizing irradiation, or treatment with iron, t-butylhydroperoxide, or glucocorticoids were unsuccessful.
To identify genes involving hearing and deafness, Skvorak et al. (1997) constructed and screened a human fetal cochlear cDNA library. From this library they isolated a cDNA corresponding to ATQ1. The plant homolog of ATQ1 was thought to be involved in regulating turgor pressure, a function that also would be essential for cells of the mammalian cochlea. Northern blots of 13 human fetal tissues showed antiquitin to be highly expressed in cochlea, ovary, eye, heart, and kidney. Using RT-PCR of rat cochlear hair cell-specific cDNA libraries, Skvorak et al. (1997) detected antiquitin expression in outer hair cells, but not in inner or vestibular type 1 hair cells, suggesting that antiquitin is not expressed ubiquitously in the cochlea.
The ALDH7A1 gene encodes a 510-amino acid protein (Mills et al., 2006).
The ALDH7A1 gene contains 18 exons (Mills et al., 2006).
Using fluorescence in situ hybridization, Skvorak et al. (1997) mapped the human ALDH7A1 gene to chromosome 5q31. The mouse homolog was mapped to mouse chromosome 18 by SSCP mapping of interspecific backcross progeny DNAs. Four human antiquitin-like sequences, possibly pseudogenes, were also identified and mapped.
In patients with early-onset vitamin B6-dependent epilepsy-4 (EPEO4; 266100), also known as pyridoxine-dependent epilepsy (EPD), Mills et al. (2006) identified homozygous or compound heterozygous mutations in the ALDH7A1 gene (107323.0001-107323.0007).
Plecko et al. (2007) investigated 18 patients with neonatal seizure onset who had been classified as having definite (11), probable (4), or possible (3) pyridoxine-dependent epilepsy. All patients had elevated pipecolic acid (PA) and alpha-amino adipic semialdehyde (AASA) in plasma and urine while on treatment with individual dosages of pyridoxine. Within this cohort, molecular analysis identified 10 novel mutations (6 missense mutations, 1 nonsense mutation, 2 splice site mutations) within highly conserved regions of the antiquitin gene. Seven mutations were located in exonic sequences and 2 in introns 7 and 17. A novel deletion of exon 7 was identified also. The E399Q mutation (107323.0001) was found with marked prevalence, accounting for 12 of 36 alleles (33%) in this study.
Salomons et al. (2007) identified a homozygous E399Q mutation in the ALDH7A1 gene in 7 patients from 4 apparently unrelated Dutch families with pyridoxine-dependent epilepsy (Been et al., 2005; Bok et al., 2007).
Using CRISPR/Cas9 gene editing, Pena et al. (2017) generated an aldh7a1-null zebrafish model that recapitulated the clinical and biochemical features of EPD. Beginning at 10 days postfertilization, mutant larvae displayed features consistent with an epilepsy phenotype, including spontaneous and recurrent seizures, epileptoform electrographic activity, and early death. Treatment with pyridoxine and pyridoxal 5-prime phosphate (PLP) extended life span in mutant larvae, and pyridoxine treatment also alleviated the manifestation of seizures. Mass spectrometry revealed accumulation of EPD biomarkers, including AASA and piperideine-6-carboxylate (P6C), B6 vitamin deficiency, and low gamma-aminobutyric acid levels in mutant fish, indicating that the ablation of aldh7a1 disrupted lysine degradation. Lysine supplementation aggravated the epilepsy phenotype in mutant larvae, inducing earlier seizure onset and death. Combination supplementation with pyridoxine and lysine suggested the existence of a critical 'seizure-inducing' level for AASA/P6C that was reached more rapidly with lysine supplementation.
In an Austrian child with early-onset vitamin B6-dependent epilepsy-4 (EPEO4; 266100), Mills et al. (2006) identified a homozygous 1195G-C transversion in exon 14 of the ALDH7A1 gene, resulting in a glu399-to-gln (E399Q) substitution. Another affected child of Dutch descent was compound heterozygous for E399Q and R82X (107323.0002). In vitro functional expression studies in Chinese hamster ovary cells showed that the mutant enzyme had no detectable activity.
In a study by Plecko et al. (2007) involving 18 patients with neonatal seizure onset, the E399Q mutation accounted for 12 of 36 alleles.
Salomons et al. (2007) identified a homozygous E399Q mutation in 7 Dutch patients from 4 apparently unrelated families with pyridoxine-dependent epilepsy. The patients had previously been reported by Been et al. (2005) and Bok et al. (2007).
In a Bosnian child with early-onset vitamin B6-dependent epilepsy-4 (EPEO4; 266100), who was born of consanguineous parents, Mills et al. (2006) identified a homozygous C-to-T transition in exon 4 of the ALDH7A1 gene, resulting in an arg82-to-ter (R82X) substitution. Another affected child of Dutch descent was compound heterozygous for R82X and E399Q (107323.0001). In vitro functional expression studies in Chinese hamster ovary cells showed that the mutant enzyme had no detectable activity.
In a dizygotic twin brother and sister with early-onset vitamin B6-dependent epilepsy-4 (EPEO4; 266100), who were born of consanguineous Turkish parents, Mills et al. (2006) identified a homozygous 434G-C transversion in the ALDH7A1 gene, resulting in a splice site mutation (IVS5-1G-C) that would skip exon 6 and a protein lacking residues 145 to 189.
In 2 sibs with early-onset vitamin B6-dependent epilepsy-4 (EPEO4; 266100), who were born of consanguineous Arab parents, Mills et al. (2006) identified a homozygous 228T-A transversion in the ALDH7A1 gene, resulting in a splice site mutation (IVS3DS+2T-A).
In a child with early-onset vitamin B6-dependent epilepsy-4 (EPEO4; 266100), who was born of consanguineous Turkish parents, Mills et al. (2006) identified a homozygous C-to-T transition in exon 6 of the ALDH7A1 gene, resulting in an ala171-to-val (A171V) substitution. In vitro functional expression studies in Chinese hamster ovary cells showed that the mutant enzyme had no detectable activity.
In 2 sibs with early-onset vitamin B6-dependent epilepsy-4 (EPEO4; 266100), who were born of consanguineous Turkish parents, Mills et al. (2006) identified a homozygous 1-bp deletion (1512delG) in exon 18 of the ALDH7A1 gene, resulting in a change in the last 7 amino acid residues of the protein and extension of the C terminus by 10 residues. In vitro functional expression studies in Chinese hamster ovary cells showed that the mutant enzyme had no detectable activity.
In 3 sibs with early-onset vitamin B6-dependent epilepsy-4 (EPEO4; 266100), who were born of consanguineous Asian parents, Mills et al. (2006) identified a homozygous T-to-G transversion in exon 14 of the ALDH7A1 gene, resulting in a tyr380-to-ter (Y380X) substitution. In vitro functional expression studies in Chinese hamster ovary cells showed that the mutant enzyme had activity that was about 1.8% of control values.
Plecko et al. (2007) described a patient with early-onset vitamin B6-dependent epilepsy-4 (EPEO4; 266100) and compound heterozygosity for mutations in the ALDH7A1 gene, a glu339-to-gln mutation (107323.0001) and an 818A-T transversion in exon 10 that resulted in an asn273-to-ile substitution (N273I).
In a Dutch patient with early-onset vitamin B6-dependent epilepsy-4 (EPEO4; 266100), Salomons et al. (2007) identified a homozygous 750G-A transition within a cryptic donor splice site 40 nucleotides upstream of the authentic splice site of intron 9 of the ALDH7A1 gene. RNA analysis showed that the cryptic site was preferentially used in the patient. In contrast, both parents who were heterozygous for the mutation showed only the presence of properly spliced mRNA, suggesting nonsense-mediated decay of the cryptic site transcript. The 750G-A mutation was shown to result in a deletion of the last 40 nucleotides of exon 9, resulting in a frameshift and premature termination. The patient also showed low levels (9%) of normally spliced ALDH7A1 transcripts, which may have accounted for slightly lower urinary and plasma AASA compared to other patients. The mutation was not detected in 210 control chromosomes.
Been, J. V., Bok, L. A., Andriessen, P., Renier, W. O. Epidemiology of pyridoxine dependent seizures in the Netherlands. Arch. Dis. Child. 90: 1293-1296, 2005. [PubMed: 16159904] [Full Text: https://doi.org/10.1136/adc.2005.075069]
Bok, L. A., Struys, E., Willemsen, M. A. A. P., Been, J. V., Jakobs, C. Pyridoxine-dependent seizures in Dutch patients: diagnosis by elevated urinary alpha-aminoadipic semialdehyde levels. Arch. Dis. Child. 92: 687-689, 2007. [PubMed: 17088338] [Full Text: https://doi.org/10.1136/adc.2006.103192]
Lee, P., Kuhl, W., Gelbart, T., Kamimura, T., West, C., Beutler, E. Homology between a human protein and a protein of the green garden pea. Genomics 21: 371-378, 1994. [PubMed: 8088832] [Full Text: https://doi.org/10.1006/geno.1994.1279]
Mills, P. B., Struys, E., Jakobs, C., Plecko, B., Baxter, P., Baumgartner, M., Willemsen, M. A. A. P., Omran, H., Tacke, U., Uhlenberg, B., Weschke, B., Clayton, P. T. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nature Med. 12: 307-309, 2006. [PubMed: 16491085] [Full Text: https://doi.org/10.1038/nm1366]
Pena, I. A., Roussel, Y., Daniel, K., Mongeon, K., Johnstone, D., Weinschutz Mendes, H., Bosma, M., Saxena, V., Lepage, N., Chakraborty, P., Dyment, D. A., van Karnebeek, C. D. M., Verhoeven-Duif, N., Bui, T. V., Boycott, K. M., Ekker, M., MacKenzie, A. Pyridoxine-dependent epilepsy in zebrafish caused by Aldh7a1 deficiency. Genetics 207: 1501-1518, 2017. [PubMed: 29061647] [Full Text: https://doi.org/10.1534/genetics.117.300137]
Plecko, B., Paul, K., Paschke, E., Stoeckler-Ipsiroglu, S., Struys, E., Jakobs, C., Hartmann, H., Luecke, T., di Capua, M., Korenke, C., Hikel, C., Reutershahn, E., Freilinger, M., Baumeister, F., Bosch, F., Erwa, W. Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene. Hum. Mutat. 28: 19-26, 2007. [PubMed: 17068770] [Full Text: https://doi.org/10.1002/humu.20433]
Salomons, G. S., Bok, L. A., Struys, E. A., Pope, L. L., Darmin, P. S., Mills, P. B., Clayton, P. T., Willemsen, M. A., Jakobs, C. An intriguing 'silent' mutation and a founder effect in antiquitin (ALDH7A1). Ann. Neurol. 62: 414-418, 2007. [PubMed: 17721876] [Full Text: https://doi.org/10.1002/ana.21206]
Skvorak, A. B., Robertson, N. G., Yin, Y., Weremowicz, S., Her, H., Bieber, F. R., Beisel, K. W., Lynch, E. D., Beier, D. R., Morton, C. C. An ancient conserved gene expressed in the human inner ear: identification, expression analysis, and chromosomal mapping of human and mouse antiquitin (ATQ1). Genomics 46: 191-199, 1997. [PubMed: 9417906] [Full Text: https://doi.org/10.1006/geno.1997.5026]