Alternative titles; symbols
HGNC Approved Gene Symbol: ADH1A
Cytogenetic location: 4q23 Genomic coordinates (GRCh38): 4:99,276,369-99,290,985 (from NCBI)
The ADH1A gene encodes the alpha subunit of class I alcohol dehydrogenase (ADH) (EC 1.1.1.1), an enzyme that catalyzes the rate-limiting step for ethanol metabolism: the oxidation of alcohol to acetaldehyde. Class 1 ADH is a homo- or heterodimeric molecule, formed by the association of 3 types of class I ADH subunits, alpha, beta (ADH1B; 103720), and gamma (ADH1C; 103730). The ADH subunit proteins belonging to class I, based on sequence and structural similarities, are closely linked within an 80-kb region on chromosome 4q22 and account for most of the ethanol-oxidizing capacity in the liver (Osier et al., 2002, Edenberg, 2007).
There are at least 5 'classes' of ADH isozymes, classified based on sequence and structural similarities, as well as preferred substrates and biochemical features (Osier et al., 2002). See ADH4 (103740), which belongs to class II; ADH5 (103710), which belongs to class III; ADH6 (103735), which belongs to class V; and ADH7 (600086), which belongs to class IV. Although the greatest similarity seen is among the class I genes, all ADH enzymes are very similar in amino acid sequence and structure (Edenberg, 2000).
The nomenclature for the ADH genes has been revised and standardized in recent years. However, there is some confusion in the literature from some groups that have used nonstandard nomenclature. The standard nomenclature approved by the HUGO Nomenclature Committee and used in the review of Edenberg (2007) is used in OMIM.
Von Bahr-Lindstrom et al. (1986) provided information on the cDNA and protein sequence of ADH1A, which encodes a deduced 375-amino acid protein including the ATG initiation codon. The structure of ADH1A is homologous to that of ADH1B and ADH1C, but also had many exchanges of functionally important residues. A beta-pleated sheet region of the coenzyme-binding domain was highly conserved between the subunits, illustrating the importance of this region.
Ikuta et al. (1986) isolated clones corresponding to the 3 class I ADH subunits from a human liver cDNA library. The ADH1A clone encodes a deduced 375-amino acid protein. The 3 subunits had a very similar amino acid identity (93 to 95% identity), but there were distinctive differences at the zinc-binding cys47 residue, reflecting differences in kinetic properties.
Hempel et al. (1985) determined the primary structures of the alpha, beta, and gamma ADH subunits. Each protein chain was found to be structurally distinct in the active site regions, where replacements affected positions that influence coenzyme binding (position 48; Gly in alpha, Arg in beta and gamma) and substrate specificity (position 49; Thr in alpha and beta, Ser in gamma).
The amino acid numbering system used above reflects inclusion of the ATG initiation codon in the ADH1A sequence (Edenberg, 2007).
Using a cDNA clone from an adult cDNA library in somatic hybrid cell studies, Smith et al. (1984) concluded that the class I ADH genes are located distal to chromosome 4q21. By Southern blot analysis of somatic hybrid cell DNAs, Smith et al. (1985) assigned the genes for alpha, beta, and gamma class I ADH to chromosome 4q21-4q25. The progression from fetal alpha to adult beta (and gamma) subunits as the predominant ones in adult life may represent an example of switching between linked genes, similar to the changes in the beta-like globin genes (see, e.g., HBB; 141900) during development. Smith (1986) stated the location of the class I ADH genes as 4q21-q24. In situ hybridization permitted a narrowing of the localization of the cluster to chromosome 4q22 (Tsukahara and Yoshida, 1989).
Yasunami et al. (1989, 1990) described the organization of the human class I alcohol dehydrogenase gene cluster on chromosome 4q22. The cluster includes ADH1A, ADH1B, and ADH1C, which are arranged in the same head-to-tail transcriptional orientation at intervals of approximately 15 kb. Genomic cloning using a cosmid vector, showed that the genes for the 3 subunits lie in an 80-kb segment in the following order: 5-prime--ADH1C--ADH1B--ADH1A--3-prime. Perhaps significantly, the order of transcriptional activation in hepatic development, alpha-to-beta-to-gamma, is opposite to the order of gene arrangement.
As outlined by Osier et al. (2002), the 7 ADH genes, encoding enzymes that catalyze the conversion of alcohols to aldehydes, exist in a cluster extending approximately 380 kb on the long arm of chromosome 4q21-q23. The class I ADH genes, renamed ADH1A, ADH1B (103720), and ADH1C (103730), exist in a tighter cluster of approximately 77 kb, flanked upstream by ADH7 (600086) and downstream by ADH6 (103735), ADH4 (103740), and ADH5 (103710), in that order.
The class I ADH genes account for most of the ethanol-oxidizing capacity in the liver (Edenberg, 2007).
Smith et al. (1971) found that ADH1A is primarily active in the liver in early fetal life, becoming less active later in gestation and only weakly active during adult life when beta subunits and, to a lesser extent, gamma subunits predominate in liver. The physiologic function for alcohol dehydrogenase in the liver is the removal of ethanol formed by microorganisms in the intestinal tract.
The list of substrates on which ADH operates is large. Important drug-ethanol interactions, e.g., digitalis-ethanol, probably have their basis in this fact (Vallee, 1979).
Although polymorphism exists at the ADH1B and ADH1C loci, the ADH1A locus is believed to be monomorphic (Stamatoyannopoulos et al., 1975).
Fetal Alcohol Syndrome
Crabb (1990) raised the possibility that polymorphism in the several alcohol dehydrogenase genes might be related to risk of fetal alcohol syndrome (FAS). A genetic influence in fetal alcohol syndrome was suggested by twin studies. Streissguth and Dehaene (1993) established that the rate of concordance for the diagnosis of fetal alcohol syndrome was 5 out of 5 for monozygotic and 7 out of 11 for dizygotic twins. In 2 DZ pairs, one twin had FAS, while the other had fetal alcohol effects (FAE). In 2 other DZ pairs, one twin had no evident abnormality, while the other had FAE. IQ scores were most similar within pairs of MZ twins and least similar within pairs of DZ twins discordant for diagnosis. Johnson et al. (1996) observed that brain and craniofacial abnormalities in fetal alcohol syndrome were predominantly symmetric and central or midline, suggesting the concept of the midline as a special developmental field, vulnerable to adverse factors during embryogenesis and fetal growth and development.
By structural analysis of the class I ADH subunits, Ikuta et al. (1986) suggested that the beta/gamma subunits and alpha subunits diverged first, and that the beta and gamma subunits diverged later in evolution.
Yokoyama et al. (1987) presented a phylogenetic tree for the alpha, beta, and gamma ADH subunits, and showed that the alpha and beta subunits diverged most recently. Their common ancestor diverged from the ancestor of the gamma subunit earlier. The evolutionary rates of nucleotide substitution for the 3 subunits showed that the gamma subunit is evolving at the slowest rate, followed by beta and alpha, in that order, implying that the gamma subunit may be providing the original function of ethanol metabolism.
Trezise et al. (1989) cloned and sequenced cDNA encoding baboon liver alcohol dehydrogenase. From the sequence they concluded that baboon liver class I ADH is of the same ancestral lineage as human ADH1B; 363 of 374 residues in the mature human and baboon proteins were identical. They estimated that the primate class I ADH gene duplication predated the primate radiation and that the alpha/beta-gamma separation of human ADH genes occurred about 60 million years ago.
Historically, class I ADH isozymes were found to be pyrazole-sensitive and basic; class II isozymes were less pyrazole-sensitive and less basic; and class III isozymes showed anodal electrophoretic mobility and low ethanol dehydrogenase activity (Smith et al., 1971).
The ADH enzyme from horse liver is a dimer with 2 very similar chains, one referred to a 'E' for ethanol-active and the other as 'S' for steroid-active. Sequence data on the horse liver enzyme were given in the atlas by Dayhoff (1972).
Adinolfi, A., Hopkinson, D. A. Blue sepharose chromatography of human alcohol dehydrogenase: evidence for interlocus and interallelic differences in affinity characteristics. Ann. Hum. Genet. 41: 399-407, 1978. [PubMed: 655629] [Full Text: https://doi.org/10.1111/j.1469-1809.1978.tb00910.x]
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Crabb, D. W. Biological markers for increased risk of alcoholism and for quantitation of alcohol consumption. J. Clin. Invest. 85: 311-315, 1990. [PubMed: 2298906] [Full Text: https://doi.org/10.1172/JCI114439]
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Edenberg, H. J. Regulation of the mammalian alcohol dehydrogenase genes. Prog. Nucleic Acid Res. Molec. Biol. 64: 295-341, 2000. [PubMed: 10697413] [Full Text: https://doi.org/10.1016/s0079-6603(00)64008-4]
Edenberg, H. J. The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res. Health 30: 5-13, 2007. [PubMed: 17718394]
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Johnson, V. P., Swayze, V. W., II, Sato, Y., Andreasen, N. C. Fetal alcohol syndrome: craniofacial and central nervous system manifestations. Am. J. Med. Genet. 61: 329-339, 1996. [PubMed: 8834044] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960202)61:4<329::AID-AJMG6>3.0.CO;2-P]
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Murray, R. F., Jr., Price, P. H. Ontogenetic, polymorphic, and interethnic variation in the isoenzymes of human alcohol dehydrogenase. Ann. N.Y. Acad. Sci. 197: 68-72, 1972. [PubMed: 4504607] [Full Text: https://doi.org/10.1111/j.1749-6632.1972.tb28121.x]
Osier, M. V., Pakstis, A. J., Soodyall, H., Comas, D., Goldman, D., Odunsi, A., Okonofua, F., Parnas, J., Schulz, L. O., Bertranpetit, J., Bonne-Tamir, B., Lu, R.-B., Kidd, J. R., Kidd, K. K. A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity. Am. J. Hum. Genet. 71: 84-99, 2002. [PubMed: 12050823] [Full Text: https://doi.org/10.1086/341290]
Smith, M., Duester, G., Bilanchone, V., Carlock, L., Hatfield, W. Derivation of probes for molecular genetic analysis of human class I alcohol dehydrogenase (ADH), a polymorphic gene family on chromosome 4. (Abstract) Am. J. Hum. Genet. 36: 153S only, 1984.
Smith, M., Duester, G., Carlock, L., Wasmuth, J. Assignment of ADH1, ADH2 and ADH3 genes (class I ADH) to human chromosome 4q21-4q25, through use of DNA probes. (Abstract) Cytogenet. Cell Genet. 40: 748 only, 1985.
Smith, M., Hopkinson, D. A., Harris, H. Developmental changes and polymorphism in human alcohol dehydrogenase. Ann. Hum. Genet. 34: 251-272, 1971. [PubMed: 5548434] [Full Text: https://doi.org/10.1111/j.1469-1809.1971.tb00238.x]
Smith, M., Hopkinson, D. A., Harris, H. Studies on the properties of the human alcohol dehydrogenase isozymes determined by the different loci ADH(1), ADH(2) and ADH(3). Ann. Hum. Genet. 37: 49-67, 1973. [PubMed: 4796765] [Full Text: https://doi.org/10.1111/j.1469-1809.1973.tb01814.x]
Smith, M., Hopkinson, D. A., Harris, H. Studies on the subunit structure and molecular size of the human dehydrogenase isozymes determined by the different loci, ADH(1), ADH(2), and ADH(3). Ann. Hum. Genet. 36: 401-414, 1973. [PubMed: 4748759] [Full Text: https://doi.org/10.1111/j.1469-1809.1973.tb00604.x]
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Trezise, A. E. O., Godfrey, E. A., Holmes, R. S., Beacham, I. F. Cloning and sequencing of cDNA encoding baboon liver alcohol dehydrogenase: evidence for a common ancestral lineage with the human alcohol dehydrogenase beta subunit and for class I ADH gene duplications predating primate radiation. Proc. Nat. Acad. Sci. 86: 5454-5458, 1989. [PubMed: 2748595] [Full Text: https://doi.org/10.1073/pnas.86.14.5454]
Tsukahara, M., Yoshida, A. Chromosomal assignment of the alcohol dehydrogenase cluster locus to human chromosome 4q21-23 by in situ hybridization. Genomics 4: 218-220, 1989. [PubMed: 2737681] [Full Text: https://doi.org/10.1016/0888-7543(89)90304-2]
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Von Wartburg, J. P., Schurch, P. M. Atypical human liver alcohol dehydrogenase. Ann. N.Y. Acad. Sci. 151: 936-947, 1968. [PubMed: 4313164] [Full Text: https://doi.org/10.1111/j.1749-6632.1968.tb48280.x]
Yasunami, M., Kikuchi, I., Sarapata, D. E., Yoshida, A. The organization of human class I alcohol dehydrogenase gene cluster. (Abstract) Cytogenet. Cell Genet. 51: 1113 only, 1989.
Yasunami, M., Kikuchi, I., Sarapata, D., Yoshida, A. The human class I alcohol dehydrogenase gene cluster: three genes are tandemly organized in an 80-kb-long segment of the genome. Genomics 7: 152-158, 1990. [PubMed: 2347582] [Full Text: https://doi.org/10.1016/0888-7543(90)90535-3]
Yokoyama, S., Yokoyama, R., Rotwein, P. Molecular characterization of cDNA clones encoding the human alcohol dehydrogenase beta-1 and the evolutionary relationship to the other class I subunits alpha and gamma. Jpn. J. Genet. 62: 241-256, 1987.