Alternative titles; symbols
HGNC Approved Gene Symbol: DAO
Cytogenetic location: 12q24.11 Genomic coordinates (GRCh38): 12:108,880,092-108,901,043 (from NCBI)
The DAO gene encodes D-amino acid oxidase (EC 1.4.3.3), one of the principal and characteristic flavoenzymes of peroxisomes found in the liver, kidney, and brain of many mammalian species. DAO has a flavin adenine dinucleotide (FAD) as the prosthetic group and catalyzes the oxidative deamination of a wide range of D-amino acids but is inactive on naturally occurring L-amino acids (summary by Barker and Hopkinson, 1977).
Fukui and Miyake (1992) isolated genomic clones for the entire DAO gene from human placental genomic libraries, with the aid of a previously cloned cDNA with human DAO as a probe. The 347-amino acid protein has a molecular mass of 39.4 kD. They noted that DAO has been intracellularly localized to peroxisomes.
Mitchell et al. (2010) found expression of the DAO gene in gray matter of the spinal cord and cerebellum, including motor neurons and Purkinje cells, respectively. DAO was also expressed in glial cells but not in the motor cortex. DAO contains FAD binding and dimer interaction domains, as well as a TrkA potassium uptake signature, an aminoacyl-tRNA synthetase class I signature, and a D-amino acid oxidase signature.
Fukui and Miyake (1992) determined that the DAO gene contains 11 exons and spans 20 kb.
With the use of genomic DNAs prepared from human/Chinese hamster somatic hybrid cells as templates for PCR, Fukui and Miyake (1992) localized the DAO gene to human chromosome 12.
The DAO gene maps to chromosome 12q24 (Mitchell et al., 2010).
Barker and Hopkinson (1977) found neither polymorphisms nor rare genetic variants of the DAO gene, which they abbreviated DAMOX. The biologic role of DAO and DDO (124450) has been thought to be protection against L-amino acids of fungi, bacteria and insects, or contribution to acid-base balance in the kidney. Alternatively, they may be merely fossil enzymes, i.e., relics of our evolutionary past.
DAAO is expressed in human brain, where it oxidizes D-serine, a potent activator of N-methyl-D-aspartate (NMDA)-type glutamate receptor (see 602717). Using yeast 2-hybrid analysis, Chumakov et al. (2002) identified DAAO as an interacting partner of the G72 protein (607408). The interaction between G72 and DAAO was confirmed in vitro and shown to result in activation of DAAO.
Molla et al. (2006) characterized recombinant human DAAO expressed in E. coli. The recombinant protein was catalytically active and converted the oxidized form of the FAD cofactor to the reduced state following addition of D-alanine under anaerobic conditions. Gel permeation chromatography revealed that native DAAO was a dimer in solution, and each monomer noncovalently bound FAD. DAAO showed higher catalytic efficiency and substrate affinity toward D-alanine and D-proline than D-serine. It also oxidized D-aspartate and glycine, but it had low affinity for these substrates. Steady-state and presteady-state measurements indicated that DAAO followed a sequential kinetic mechanism.
Associations Pending Confirmation
Chumakov et al. (2002) found 4 single nucleotide polymorphism (SNP) markers from DAAO that were associated with schizophrenia (181500) in the same Canadian case/control samples that led to the identification of G72. Logistic regression revealed genetic interaction between associated SNPs in the vicinity of 2 genes. Chumakov et al. (2002) concluded that association of both DAAO and G72 with schizophrenia, together with activation of DAAO by a G72 protein product, pointed to the involvement of this N-methyl-D-aspartate receptor regulation pathway in schizophrenia.
In a 3-generation kindred with familial amyotrophic lateral sclerosis (ALS; 105400), Mitchell et al. (2010) found linkage to markers D12S1646 and D12S354 on chromosome 12q24 (2-point lod score of 2.7). Screening of candidate genes identified a heterozygous arg199-to-trp (R199W) mutation in exon 7 of the DAO gene in 3 affected members and in 1 obligate carrier who died at age 73 years of cardiac failure and reportedly had right-sided weakness and dysarthria. The proband had onset at age 40, and the mean age at death in 7 cases was 44 years (range, 42 to 55 years). The R199W mutation was also present in 3 at-risk individuals of 33, 44, and 48 years of age, respectively. Arg199 is highly conserved between mammalian and lower organisms such as yeast, fungi, and bacteria, and lies close to the FAD-binding site. The mutation was not found in 780 Caucasian controls. Postmortem examination of the obligate carrier showed some loss of motor neurons in the spinal cord and degeneration of 1 of the lateral corticospinal tracts. There was markedly decreased DAO enzyme activity in the spinal cord compared to controls. Coexpression of mutant protein with wildtype protein in COS-7 cells indicated a dominant-negative effect of the mutant protein. Rat neuronal cell lines expressing mutant protein showed decreased viability and increased ubiquitinated aggregates compared to wildtype. A pathogenic role for the accumulation of D-serine was postulated. Mitchell et al. (2010) suggested a role for the DAO gene in ALS but noted that a causal role for the R199W-mutant protein remained to be unequivocally established.
Millecamps et al. (2010) sequenced the DAO gene in 126 unrelated French patients with familial ALS and identified a heterozygous arg38-to-his (R38H) variant in exon 2 in a mother and daughter with classic adult-onset ALS. The variant was also found in 1 of 1,016 control chromosomes, indicating that it is a rare polymorphism. They did not find the R199W variant in their patients. Millecamps et al. (2010) stated that their data neither confirmed nor excluded the possibility that DAO mutations may be associated with ALS in rare families. In a reply, de Belleroche and Morris (2010) noted that the data reported by Millecamps et al. (2010) should not alter the interpretation of their previous findings (Mitchell et al., 2010), which showed that the R199W mutation segregated with disease, promoted formation of ubiquitinated protein aggregates, and reduced motor neuron survival.
Inhibition or disruption of Dao leads to increased levels of D-serine in the mouse brain, serum, and spinal cord, and is associated with increased NMDA-mediated excitatory postsynaptic currents. Zhang et al. (2011) found that Dao-null mice had enhanced prepulse inhibition (PPI) compared to controls. When treated with a competitive NMDA antagonist, the mutant mice had increased sensitivity to the PPI-disruptive effect. Mutant mice also showed increased learning and exploratory behavior that was not related to anxiety. The findings suggested that Dao-null mice might have altered functioning of NMDA receptors due to increased amounts of D-serine, but there was only modest support for manipulations of DAO activity as a potential therapeutic approach to treat schizophrenia.
Barker, R. F., Hopkinson, D. A. The genetic and biochemical properties of the D-amino acid oxidases in human tissues. Ann. Hum. Genet. 41: 27-42, 1977. [PubMed: 21608] [Full Text: https://doi.org/10.1111/j.1469-1809.1977.tb01959.x]
Chumakov, I., Blumenfeld, M., Guerassimenko, O., Cavarec, L., Palicio, M., Abderrahim, H., Bougueleret, L., Barry, C., Tanaka, H., La Rosa, P., Puech, A., Tahri, N., and 51 others. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc. Nat. Acad. Sci. 99: 13675-13680, 2002. Note: Erratum: Proc. Nat. Acad. Sci. 99: 17221 only, 2002. [PubMed: 12364586] [Full Text: https://doi.org/10.1073/pnas.182412499]
de Belleroche, J., Morris, A. Reply to Millecamps et al.: elucidating the role of D amino oxidase in familial amyotrophic sclerosis. Proc. Nat. Acad. Sci. 107: E108, 2010. Note: Electronic Article.
Fukui, K., Miyake, Y. Molecular cloning and chromosomal localization of a human gene encoding D-amino-acid oxidase. J. Biol. Chem. 267: 18631-18638, 1992. [PubMed: 1356107]
Millecamps, S., Da Barroca, S., Cazeneuve, C., Salachas, F., Pradat, P.-F., Danel-Brunaud, V., Vandenberghe, N., Lacomblez, L., Le Forestier, N., Bruneteau, G., Camu, W., Brice, A., Meininger, V., LeGuern, E. Questioning on the role of D amino acid oxidase in familial amyotrophic lateral sclerosis. Proc. Nat. Acad. Sci. 107: E107, 2010. Note: Electronic Article. [PubMed: 20538972] [Full Text: https://doi.org/10.1073/pnas.1006190107]
Mitchell, J., Paul, P., Chen, H.-J., Morris, A., Payling, M., Falchi, M., Habgood, J., Panoutsou, S., Winkler, S., Tisato, V., Hajitou, A., Smith, B., Vance, C., Shaw, C., Mazarakis, N. D., de Belleroche, J. Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase. Proc. Nat. Acad. Sci. 107: 7556-7561, 2010. [PubMed: 20368421] [Full Text: https://doi.org/10.1073/pnas.0914128107]
Molla, G., Sacchi, S., Bernasconi, M., Pilone, M. S., Fukui, K., Pollegioni, L. Characterization of human D-amino acid oxidase. FEBS Lett. 580: 2358-2364, 2006. [PubMed: 16616139] [Full Text: https://doi.org/10.1016/j.febslet.2006.03.045]
Zhang, M., Ballard, M. E., Basso, A. M., Bratcher, N., Browman, K. E., Curzon, P., Konno, R., Meyer, A. H., Rueter, L. E. : Behavioral characterization of a mutant mouse strain lacking D-amino acid oxidase activity. Behav. Brain Res. 217: 81-87, 2011. [PubMed: 20933022] [Full Text: https://doi.org/10.1016/j.bbr.2010.09.030]