Alternative titles; symbols
HGNC Approved Gene Symbol: MAOB
Cytogenetic location: Xp11.3 Genomic coordinates (GRCh38): X:43,766,610-43,882,450 (from NCBI)
The MAOB gene encodes monoamine oxidase B. Two monoamine oxidase (EC 1.4.3.4) isoenzymes, MAOA (309850) and MAOB, catalyze the oxidative deamination of neuroactive and vasoactive amines, as well as the oxidation of several xenobiotics. MAOA and MAOB are present in the outer mitochondrial membrane in the central nervous system and peripheral tissues. MAOA, the primary type in fibroblasts, preferentially degrades serotonin and norepinephrine. MAOB, the primary type found in platelets and leukocytes, preferentially degrades phenylethylamine and benzylamine (summary by Bach et al., 1988).
Bach et al. (1988) isolated clones corresponding to the MAOA and MAOB genes from a human liver cDNA library. The MAOB gene encodes a 520-amino acid protein with a molecular mass of 58.8 kD and shows 70% amino acid identity to MAOA. Both sequences contained the pentapeptide ser-gly-gly-cys-tyr, in which the obligatory cofactor FAD is covalently bound to cysteine. The 2 proteins appeared to be derived from separate genes.
Chen et al. (1993) determined that MAOB sequences from human platelets, liver, and frontal cortex were identical except for 3 silent variants that differed in the frontal cortex. The deduced amino acid sequences of MAOB from all 3 sources was identical.
Grimsby et al. (1991) found that MAOA and MAOB genes isolated from X chromosome-specific libraries span at least 60 kb, consist of 15 exons, and show identical exon-intron organization. Exon 12 coded for the covalent FAD-binding-site and is the most conserved exon; the MAOA and MAOB exon 12 products share 93.9% peptide identity. These results suggested that MAOA and MAOB are derived from duplication of a common ancestral gene.
Rice et al. (1984) presented data that they interpreted as evidence for a single major locus. Kochersperger et al. (1986) concluded that both MAOA and MAOB are coded by X-linked genes. They used specific monoclonal antibodies for each to distinguish the 2 forms of MAO from each other and from the corresponding mouse enzymes in mouse-human hybrids.
Levy et al. (1989) localized the MAOA gene to Xp11.4-p11.23 by in situ hybridization using a cDNA probe. They presented evidence that this localization reflects the positions of the genes for both A and B forms of the enzyme.
By characterizing a 265-kb YAC containing sequences for the MAOA and MAOB genes, Chen et al. (1992) localized these 2 genes within a 240-kb region of Xp11.23 and showed that they are arranged in a tail-to-tail configuration, with the 3-prime coding sequences separated by about 50 kb. The combined information supports the order of markers within this region to be DXS77-DXS7-MAOA-MAOB.
As Weinshilboum (1983) pointed out, the genetic control of 3 enzymes involved in human catecholamine metabolism was then known: dopamine beta-hydroxylase (DBH; 609312), a synthetic enzyme, catechol-O-methyltransferase (COMTl; 116790) and monoamine oxidases A (309850) and B, metabolic enzymes. MAO is classified as A or B on the basis of differential substrate specificities and differential sensitivity to inhibitors.
Fowler et al. (1996) found that brains of living smokers showed a 40% decrease in the level of monoamine oxidase B, relative to nonsmokers or former smokers. MAO-B is involved in the breakdown of dopamine, a neurotransmitter implicated in reinforcing and motivating behaviors as well as movement. MAO-B inhibition is, therefore, associated with enhanced activity of dopamine, as well as with decreased production of hydrogen peroxide, a source of reactive oxygen species. Fowler et al. (1996) suggested that the observation may bear a relationship to the addictive nature of smoking, to the high prevalence of smoking in association with psychiatric disorders, and the decreased risk of Parkinson disease (PD; 168600) in smokers. They suggested that MAOB inhibitory drugs might be useful as an adjunct in smoking cessation and, in a note added in proof, observed that a reversible MAOA inhibitor facilitates the cessation of smoking in highly dependent smokers.
Binda et al. (2002) determined the structure of human MAOB to 3-angstrom resolution. The enzyme binds to a membrane through a C-terminal transmembrane helix and apolar loops located at various positions in the sequence. The active site of MAOB consists of a 420-angstrom-hydrophobic substrate cavity interconnected to an entrance cavity of 290 angstroms. The recognition site for the substrate amino group is an aromatic cage formed by tyr398 and tyr435.
Weinshilboum (1979) reviewed the biochemical genetics of platelet monoamine oxidase. He found strong evidence of heritability but no clear mode of inheritance. Studies using benzylamine as substrate show approximately equal numbers of subjects with high and low enzyme activity. Goldin et al. (1982) could not show platelet MAO activity to be segregating as a single major gene. On the other hand, they could reject a purely nongenetic hypothesis. The study of Rice et al. (1984) incorporated the data of Goldin et al. (1982) with other data. They concluded that the frequency of the high-MAO allele is about 0.25, which is at odds with the suggestion that low MAO is an indicator for schizophrenia which has a lifetime risk of only 0.85%.
Checkoway et al. (1998) investigated the interaction between cigarette smoking and a genetic polymorphism in intron 13 of the MOAB gene with relation to Parkinson disease (PD; 168600) risk. Smoking elevated the risk of developing PD for those individuals who carried the A allele, but reduced the risk of developing Parkinson disease in individuals with the G allele.
Wu et al. (2001) analyzed 224 Taiwanese patients with PD for MAOB intron 13 G and COMT L (V158M; 116790.0001) polymorphisms and found that the MAOB G genotype (G in men, G/G in women) was associated with a 2.07-fold increased relative risk for PD, an association which was stronger for men than for women. Although COMT polymorphism alone was not associated with an increased risk for PD, when it was considered in conjunction with the MAOB G genotype, there was a 2.4-fold increased relative risk for PD. In men, the combined alleles, MAOB G and COMT L, increased the relative risk for PD to 7.24. Wu et al. (2001) suggested that, in Taiwanese, the development of PD may be related to the interaction of 2 or more genes involved in dopamine metabolism.
Lenders et al. (1996) reported on 2 subjects with a hitherto undescribed selective deficiency of MAOB due to a microdeletion of the X chromosome, extending from the Norrie disease locus (ND; 310600) to within the MAOB gene; the order of the 3 genes on Xp is tel--5-prime MAOA--3-prime MAOB--3-prime ND--cen. Comparisons of the neurochemical characteristics of previously described patients with combined MAO-AB deficiency and selective MAOA deficiency were reported in greater detail, including a comprehensive analysis of plasma catecholamine metabolites. These comparisons enabled examination of the relative roles of MAOA and MAOB in the metabolic degradation of catecholamines and other biogenic amines, including serotonin and the trace amines. The MAOB deficient subjects were 2 brothers, aged 29 and 31 years, in whom Norrie disease, characterized by blindness, was diagnosed at the ages of 5 and 18 months. Progressive hearing loss due to cochlear degeneration was noted in adolescence. Lenders et al. (1996) demonstrated that in these brothers with only MAOB deficiency in association with ND, the distal break occurred in intron 5 of the MAOB gene with the deletion extending proximally into the ND gene. In contrast to the borderline mental retardation and abnormal behavioral phenotype in subjects with selective MAOA deficiency and the severe mental retardation in patients with combined MAOA/MAOB deficiency and Norrie disease, the MAOB deficient subjects exhibited neither abnormal behavior nor mental retardation. Distinct neurochemical profiles characterized the 3 groups of MAO-deficient patients. In MAOA-deficient subjects, there was a marked decrease in deaminated catecholamine metabolites and a concomitant marked elevation of O-methylated amine metabolites. These neurochemical changes were only slightly exaggerated in patients with combined lack of the 2 forms of MAO. In contrast, the only biochemical abnormalities detected in subjects with the MAOB gene deletion were a complete absence of platelet MAO activity and an increased urinary excretion of phenylethylamine. The differences indicated to the authors that, under normal conditions, MAOA is considerably more important than MAOB in the metabolism of biogenic amines, a factor likely to contribute to the different clinical phenotypes.
Whibley et al. (2010) reported 2 Caucasian brothers with a 240-kb deletion of chromosome Xp11.4-p11.3 that encompassed exons 2 through 15 of the MAOA gene and all exons of the MAOB gene. The NDP gene (300658) was not involved. They had severe developmental delay, mental retardation, seizures, and hang-wringing/lip-smacking behavior. Both had hypotonia in infancy, with worsening episodic hypotonia resembling seizures. The older boy had recurrent screaming episodes with head banging, self scratching of the face, and chewing of the hands. He died unexpectedly at age 5 years. The other boy had episodes of restlessness followed by hypotonia and loss of consciousness. At age 15 years, he could walk, run clumsily, and was social, using single words and sign language. Both had mild facial dysmorphism, with epicanthal folds and long eyelashes, The unaffected mother was a heterozygous carrier of the deletion. Detailed analysis of the deletion indicated that the proximal breakpoint occurred in an L1PA7 LINE element and the distal breakpoint within an AluY element; the authors suggested the occurrence of a nonhomologous end-joining (NHEJ) event. Whibley et al. (2010) concluded that both MAO genes are critical for early brain development and function, since both of their patients had severe to profound mental retardation appearing shortly after birth. This was in contrast to the report of Lenders et al. (1996), who found that loss of only MAOB results in no intellectual impairment, and patients with loss of only MAOA, who have milder mental retardation (see Brunner et al., 1993 and 300615).
Grimsby et al. (1997) demonstrated that targeted inactivation of MAOB in mice increased levels of beta-phenylethylamine (PEA) but not those of serotonin, norepinephrine, or dopamine, demonstrating a primary role for MAOB in the metabolism of PEA. Other work had implicated PEA in modulating mood and affect. Indeed, MAOB-deficient mice showed an increased reactivity to stress. In addition, mutant mice were resistant to the neurodegenerative effects of MPTP, a toxin that induces a condition reminiscent of Parkinson disease.
Chen et al. (2004) identified, bred, and characterized a line of Maoa/Maob double-knockout mice that arose by spontaneous point mutation in Maoa exon 8 in a litter of Maob knockout mice. Double-knockout mice showed reduced body weight compared with wildtype mice. Brain levels of serotonin, norepinephrine, dopamine, and phenylethylamine increased and levels of the serotonin metabolite 5-hydroxyindoleacetic acid decreased to a much greater degree than in either Maoa or Maob single-knockout mice. Chase/escape and anxiety-like behavior in the double-knockout mice differed from that in Maoa or Maob single-knockout mice, suggesting that varying monoamine levels result in both a unique biochemical and behavioral phenotype.
MAO has been of particular interest to psychiatry and genetics because of the suggestion by Wyatt et al. (1973) that low activity is a 'genetic marker' for schizophrenia.
Bach, A. W., Lan, N. C., Johnson, D. L., Abell, C. W., Bembenek, M. E., Kwan, S.-W., Seeburg, P. H., Shih, J. C. cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. Proc. Nat. Acad. Sci. 85: 4934-4938, 1988. [PubMed: 3387449] [Full Text: https://doi.org/10.1073/pnas.85.13.4934]
Binda, C., Newton-Vinson, P., Hubalek, F., Edmondson, D. E., Mattevi, A. Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nature Struct. Biol. 9: 22-26, 2002. [PubMed: 11753429] [Full Text: https://doi.org/10.1038/nsb732]
Brunner, H. G., Nelen, M. R., van Zandvoort, P., Abeling, N. G. G. M., van Gennip, A. H., Wolters, E. C., Kuiper, M. A., Ropers, H. H., van Oost, B. A. X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism. Am. J. Hum. Genet. 52: 1032-1039, 1993. [PubMed: 8503438]
Checkoway, H., Franklin, G. M., Costa-Mallen, P., Smith-Weller, T., Dilley, J., Swanson, P. D., Costa, L. G. A genetic polymorphism of MAO-B modifies the association of cigarette smoking and Parkinson's disease. Neurology 50: 1458-1461, 1998. [PubMed: 9596006] [Full Text: https://doi.org/10.1212/wnl.50.5.1458]
Chen, K., Holschneider, D. P., Wu, W., Rebrin, I., Shih, J. C. A spontaneous point mutation produces monoamine oxidase A/B knock-out mice with greatly elevated monoamines and anxiety-like behavior. J. Biol. Chem. 279: 39645-39652, 2004. [PubMed: 15272015] [Full Text: https://doi.org/10.1074/jbc.M405550200]
Chen, K., Wu, H.-F., Shih, J. C. The deduced amino acid sequences of human platelet and frontal cortex monoamine oxidase B are identical. J. Neurochem. 61: 187-190, 1993. [PubMed: 8515265] [Full Text: https://doi.org/10.1111/j.1471-4159.1993.tb03554.x]
Chen, Z.-Y., Powell, J. F., Hsu, Y.-P. P., Breakefield, X. O., Craig, I. W. Organization of the human monoamine oxidase genes and long-range physical mapping around them. Genomics 14: 75-82, 1992. [PubMed: 1427833] [Full Text: https://doi.org/10.1016/s0888-7543(05)80286-1]
Denney, R. M., Fritz, R. R., Patel, N. T., Abell, C. W. Human liver MAO-A and MAO-B separated by immunoaffinity chromatography with MAO-B-specific monoclonal antibody. Science 215: 1400-1403, 1982. [PubMed: 7063850] [Full Text: https://doi.org/10.1126/science.7063850]
Fowler, J. S., Volkow, N. D., Wang, G.-J., Pappas, N., Logan, J., MacGregor, R., Alexoff, D., Shea, C., Schlyer, D., Wolf, A. P., Warner, D., Zezulkova, I., Cilento, R. Inhibition of monoamine oxidase B in the brains of smokers. Nature 379: 733-736, 1996. [PubMed: 8602220] [Full Text: https://doi.org/10.1038/379733a0]
Goldin, L. R., Gershon, E. S., Lake, C. R., Murphy, D. L., McGinniss, M., Sparkes, R. S. Segregation and linkage studies of plasma dopamine-beta-hydroxylase (DBH), erythrocyte catechol-O-methyltransferase (COMT), and platelet monoamine oxidase (MAO): possible linkage between the ABO locus and a gene controlling DBH activity. Am. J. Hum. Genet. 34: 250-262, 1982. [PubMed: 6951409]
Grimsby, J., Chen, K., Wang, L.-J., Lan, N. C., Shih, J. C. Human monoamine oxidase A and B genes exhibit identical exon-intron organization. Proc. Nat. Acad. Sci. 88: 3637-3641, 1991. [PubMed: 2023912] [Full Text: https://doi.org/10.1073/pnas.88.9.3637]
Grimsby, J., Toth, M., Chen, K., Kumazawa, T., Klaidman, L., Adams, J. D., Karoum, F., Gal, J., Shih, J. C. Increased stress response and beta-phenylethylamine in MAOB-deficient mice. Nature Genet. 17: 206-210, 1997. [PubMed: 9326944] [Full Text: https://doi.org/10.1038/ng1097-206]
Kochersperger, L. M., Parker, E. L., Siciliano, M., Darlington, G. J., Denney, R. M. Assignment of genes for human monoamine oxidases A and B to the X chromosome. J. Neurosci. Res. 16: 601-616, 1986. [PubMed: 3540317] [Full Text: https://doi.org/10.1002/jnr.490160403]
Lenders, J. W. M., Eisenhofer, G., Abeling, N. G. G. M., Berger, W., Murphy, D. L., Konings, C. H., Bleeker Wagemakers, L. M., Kopin, I. J., Karoum, F., van Gennip, A. H., Brunner, H. G. Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes. J. Clin. Invest. 97: 1010-1019, 1996. [PubMed: 8613523] [Full Text: https://doi.org/10.1172/JCI118492]
Levy, E. R., Powell, J. F., Buckle, V. J., Hsu, Y.-P. P., Breakefield, X. O., Craig, I. W. Localization of human monoamine oxidase to Xp11.23-11.4 by in situ hybridization: implications for Norrie disease. Genomics 5: 368-370, 1989. [PubMed: 2793188] [Full Text: https://doi.org/10.1016/0888-7543(89)90072-4]
Rice, J., McGuffin, P., Goldin, L. R., Shaskan, E. G., Gershon, E. S. Platelet monoamine oxidase (MAO) activity: evidence for a single major locus. Am. J. Hum. Genet. 36: 36-43, 1984. [PubMed: 6695924]
Weinshilboum, R. M. Catecholamine biochemical genetics in human populations. In: Breakefield, X. O.: Neurogenetics: Genetic Approaches to the Nervous System. New York: Elsevier/North Holland (pub.) 1979. Pp. 257-282.
Weinshilboum, R. M. Biochemical genetics of catecholamines in humans. Mayo Clin. Proc. 58: 319-330, 1983. [PubMed: 6843183]
Whibley, A., Urquhart, J., Dore, J., Willatt, L., Parkin, G., Gaunt, L., Black, G., Donnai, D., Raymond, F. L. Deletion of MAOA and MAOB in a male patient causes severe developmental delay, intermittent hypotonia and stereotypical hand movements. Europ. J. Hum. Genet. 18: 1095-1099, 2010. [PubMed: 20485326] [Full Text: https://doi.org/10.1038/ejhg.2010.41]
Wu, R. M., Cheng, C. W., Chen, K. H., Lu, S. L., Shan, D. E., Ho, Y. F., Chern, H. D. The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese. Neurology 56: 375-382, 2001. [PubMed: 11171904] [Full Text: https://doi.org/10.1212/wnl.56.3.375]
Wyatt, R. J., Murphy, D. L., Belmaker, R., Cohen, S., Donnelly, C. H., Pollin, W. Reduced monoamine oxidase activity in platelets: a possible genetic marker for vulnerability to schizophrenia. Science 179: 916-918, 1973. [PubMed: 4687789] [Full Text: https://doi.org/10.1126/science.179.4076.916]