Alternative titles; symbols
HGNC Approved Gene Symbol: ALDOA
SNOMEDCT: 1187461004;
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38): 16:30,064,279-30,070,420 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p11.2 | Glycogen storage disease XII | 611881 | Autosomal recessive | 3 |
Fructose-1,6-bisphosphate aldolase (EC 4.1.2.13) is a glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. The enzyme is a tetramer of identical 40-kD subunits. Vertebrates have 3 aldolase isozymes, aldolases A, B (ALDOB; 612724), and C (ALDOC; 103870), which are distinguished by their electrophoretic and catalytic properties. The sequence of the aldolases around the active-site lysine is highly conserved in evolution. Mammalian tissues express aldolase isozymes in a well-characterized pattern. Developing embryo produces aldolase A, which continues to be expressed in many adult tissues, sometimes at much higher levels than in embryo. In adult muscle, aldolase A can be as much as 5% of total cellular protein. In adult liver, kidney, and intestine, aldolase A expression is repressed and aldolase B is produced. In brain and other nervous tissue, aldolase A and C are expressed about equally. In transformed liver cells, aldolase A replaces aldolase B (Rottmann et al., 1984).
Electrophoretic variants of fructoaldolase were reported by Charlesworth (1972).
Sakakibara et al. (1985) cloned aldolase A from a human liver cDNA library. The deduced protein contains 363 amino acids. RNA blot analysis revealed a 1.6-kb ALDOA mRNA in skeletal muscle and a 1.7-kb ALDOA mRNA in liver and placenta.
Freemont et al. (1988) presented the complete amino acid sequence of human skeletal muscle fructose-bisphosphate aldolase, comprising 363 residues.
Izzo et al. (1988) found that the ALDOA gene spans 7.5 kb and contains 12 exons. It occurs as a single copy per haploid human genome. Eight exons containing the coding sequence were common to all mRNAs extracted from several mammalian sources. Four additional exons were identified in the 5-prime UTR: the first was contained in the ubiquitous mRNA, the second in the muscle-specific mRNA, and the third and fourth in a minor mRNA in human liver. S(1)-nuclease-protection analysis of the 5-prime end of mRNA from cultured fibroblasts, muscle, and hepatoma cell lines revealed 4 different transcription initiation sites. The presence of conventional sequences for 4 eukaryotic promoters was also demonstrated. The nucleotide similarities in the coding region and the intron-exon organization of aldolases A, B, and C confirmed that they arose from a common ancestral gene, with aldolase B diverging first.
Harris (1974) concluded that 3 loci determine aldolase. Cohen-Haguenauer et al. (1985) assigned aldolase A to chromosome 16, whereas Kukita et al. (1985) assigned it to chromosome 22. However, Kukita et al. (1987) mapped the ALDOA gene to chromosome 16 by 3 different methods: molecular hybridization to hybrid cell DNA, molecular hybridization to DNA of sorted metaphase chromosomes, and in situ hybridization. In situ hybridization indicated that the gene is located on the chromosome 16q22-q24 band. Serero et al. (1988) also assigned the aldolase A gene to chromosome 16 by Southern blot analysis of human genomic DNA with a cDNA probe. Aldolase A pseudogenes were found on chromosomes 3 and 10. The map location of the 3 aldolase genes and the aldolase pseudogene (see 612724) is of considerable interest from the point of view of chromosome evolution. The 4 genes are found on 2 pairs of morphologically similar chromosomes, 9 and 10, and 16 and 17. These homeologous (i.e., of similar origin) chromosome pairs may have arisen from 1 or 2 tetraploidization events (Comings, 1972; Ohno, 1973). As predicted by the chromosomal locations, the coding sequences of the expressed aldolase A and C genes on chromosomes 16 and 17, respectively, are more homologous to each other than either of them is to the expressed aldolase B gene on chromosome 9.
Amberger (2008) mapped the ALDOA gene to chromosome 16p11.2 based on an alignment of the ALDOA sequence (GenBank M11560) with the genomic sequence (build 36.2).
Kishi et al. (1987) studied a patient with red cell aldolase deficiency, or glycogen storage disease XII (GSD12; 611881), and identified a mutation in the ALDOA gene that resulted in an asp128-to-gly (D128G; 103850.0001) substitution in the protein. The patient's enzyme from red cells and from cultured lymphoblastoid cells was highly thermolabile, and the enzyme expressed in E. coli was likewise thermolabile. The parents had intermediate levels of red cell aldolase A. Southern blot analysis of genomic DNA showed that the patient was homozygous for a mutation that was heterozygous in both parents.
In a boy with aldolase A deficiency, Kreuder et al. (1996) identified a homozygous germline mutation in the ALDOA gene that resulted substitution of a negatively charged glutamic acid with a positively charged lysine at the highly conserved residue 206 (E206L; 103850.0002). The affected residue is highly conserved within the subunit interface region.
In a patient with red cell aldolase deficiency, or glycogen storage disease XII (GSD12; 611881), Kishi et al. (1987) identified an A-G transition at nucleotide 386 in the codon for the 128th amino acid, leading to a change from aspartic acid (GAU) to glycine (GGU) (D128G) in the aldolase protein. The patient's enzyme from red cells and from cultured lymphoblastoid cells was highly thermolabile, and the enzyme expressed in E. coli was likewise thermolabile. Since asp128 is conserved in aldolase A, B (612724), and C (103870) of eukaryotes, including Drosophila, this residue likely has a crucial role in maintaining the correct spatial structure or in performing the catalytic function of the enzyme. The parents had intermediate levels of red cell aldolase A. The change in the aspartic acid codon extinguished an Fok1 restriction site (GGATG to GGGTG). Southern blot analysis of genomic DNA showed that the patient was homozygous for a mutation that was heterozygous in both parents.
Kreuder et al. (1996) described a 4 1/2-year-old boy with predominantly myopathic symptoms of aldolase A deficiency (GSD12; 611881) due to substitution of a single amino acid within the subunit interface most essential for the tetrameric structure of the enzyme. The patient showed muscle weakness and premature muscle fatigue. He was unable to walk for more than 10 minutes or climb more than 20 steps at a time. Several unexplained episodes of jaundice and anemia required blood transfusions during the first year of life. The parents were healthy and nonconsanguineous. The patient showed slight jaundice, diminished muscle mass, reduced muscle tone, and proximal muscle weakness. The liver and spleen were somewhat enlarged. Creatine kinase was markedly elevated in the blood of this patient, and several muscle enzymes, as well as serum bilirubin, were increased. Codon 206 of the ALDOA gene was found to have a homozygous transition from GAG (glu) to AAG (lys) (E206K). The authors noted that a glutamate is present in all human aldolases at position 206 of the enzyme. Both parents and a healthy brother were heterozygous for the mutation.
Amberger, J. S. Personal Communication. Baltimore, Md. 3/6/2008.
Charlesworth, D. Starch-gel electrophoresis of four enzymes from human red blood cells: glyceraldehyde-3-phosphate dehydrogenase, fructoaldolase, glyoxalase II and sorbitol dehydrogenase. Ann. Hum. Genet. 35: 477-484, 1972. [PubMed: 5073693] [Full Text: https://doi.org/10.1111/j.1469-1809.1957.tb01873.x]
Cohen-Haguenauer, O., Van Cong, N., Mennecier, F., Kahn, A., Frezal, J. The human aldolase A gene is on chromosome 16.(Abstract) Cytogenet. Cell Genet. 40: 605, 1985.
Comings, D. E. Evidence of ancient tetraploidy and conservation of linkage groups in mammalian chromosomes. Nature 238: 455-457, 1972. [PubMed: 4561854] [Full Text: https://doi.org/10.1038/238455a0]
Freemont, P. S., Dunbar, B., Fothergill-Gilmore, L. A. The complete amino acid sequence of human skeletal-muscle fructose-bisphosphate aldolase. Biochem. J. 249: 779-788, 1988. [PubMed: 3355497] [Full Text: https://doi.org/10.1042/bj2490779]
Harris, H. Personal Communication. London, England 1974.
Izzo, P., Costanzo, P., Lupo, A., Rippa, E., Paolella, G., Salvatore, F. Human aldolase A gene: structural organization and tissue-specific expression by multiple promoters and alternate mRNA processing. Europ. J. Biochem. 174: 569-578, 1988. [PubMed: 3391172] [Full Text: https://doi.org/10.1111/j.1432-1033.1988.tb14136.x]
Kishi, H., Mukai, T., Hirono, A., Fujii, H., Miwa, S., Hori, K. Human aldolase A deficiency associated with a hemolytic anemia: thermolabile aldolase due to a single base mutation. Proc. Nat. Acad. Sci. 84: 8623-8627, 1987. [PubMed: 2825199] [Full Text: https://doi.org/10.1073/pnas.84.23.8623]
Kreuder, J., Borkhardt, A., Repp, R., Pekrun, A., Gottsche, B., Gottschalk, U., Reichmann, H., Schachenmayr, W., Schlegel, K., Lampert, F. Brief report: inherited metabolic myopathy and hemolysis due to a mutation in aldolase A. New Eng. J. Med. 334: 1100-1104, 1996. [PubMed: 8598869] [Full Text: https://doi.org/10.1056/NEJM199604253341705]
Kukita, A., Yoshida, M. C., Fukushige, S., Sakakibara, M., Joh, K., Mukai, T., Hori, K. Molecular gene mapping of human aldolase A (ALDOA) gene to chromosome 16. Hum. Genet. 76: 20-26, 1987. [PubMed: 3570299] [Full Text: https://doi.org/10.1007/BF00283044]
Kukita, A., Yoshida, M. C., Sakakibara, M., Mukai, T., Hori, K. Molecular gene mapping of the structural gene for human aldolase A (ALDOA) to chromosome 22.(Abstract) Cytogenet. Cell Genet. 40: 674, 1985.
Ohno, S. Ancient linkage groups and frozen accidents. Nature 244: 259-262, 1973. [PubMed: 4200792] [Full Text: https://doi.org/10.1038/244259a0]
Penhoet, E., Rajkumar, T., Rutter, W. J. Multiple forms of fructose diphosphate aldolase in mammalian tissues. Proc. Nat. Acad. Sci. 56: 1275-1282, 1966. [PubMed: 5230152] [Full Text: https://doi.org/10.1073/pnas.56.4.1275]
Rottmann, W. H., Tolan, D. R., Penhoet, E. E. Complete amino acid sequence for human aldolase B derived from cDNA and genomic clones. Proc. Nat. Acad. Sci. 81: 2738-2742, 1984. [PubMed: 6585824] [Full Text: https://doi.org/10.1073/pnas.81.9.2738]
Sakakibara, M., Mukai, T., Hori, K. Nucleotide sequence of a cDNA clone for human aldolase: a messenger RNA in the liver. Biochem. Biophys. Res. Commun. 131: 413-420, 1985. [PubMed: 3840020] [Full Text: https://doi.org/10.1016/0006-291x(85)91818-2]
Serero, S., Maire, P., Van Cong, N., Cohen-Haguenauer, O., Gross, M. S., Jegou-Foubert, C., de Tand, M. F., Kahn, A., Frezal, J. Localization of the active gene of aldolase on chromosome 16, and two aldolase A pseudogenes on chromosomes 3 and 10. Hum. Genet. 78: 167-174, 1988. [PubMed: 2828224] [Full Text: https://doi.org/10.1007/BF00278190]
Tolan, D. R., Niclas, J., Bruce, B. D., Lebo, R. V. Evolutionary implications of the human aldolase-A, -B, -C, and -pseudogene chromosome locations. Am. J. Hum. Genet. 41: 907-924, 1987. [PubMed: 3674018]