Monoamine oxidase A
MAOA | |||
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Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process | |||
Sources:Amigo / QuickGO |
Ensembl | |||||||||
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UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) | |||||||||
Location (UCSC) | Chr X: 43.65 – 43.75 Mb | Chr X: 16.49 – 16.55 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Monoamine oxidase A, also known as MAO-A, is an
Structures
Gene
Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the MAOA gene.[5][6] The promoter of MAOA contains conserved binding sites for
In humans, there is a 30-base
The
Protein
MAO-A shares 70%
Function
Monoamine oxidase A catalyzes
- RCH
2-Amine + O
2 + H
2O → R-Aldehyde + H
2O
2 + NH
3
This reaction is believed to occur in three steps, using FAD as an electron-transferring cofactor. First, the amine is oxidized to the corresponding
Compared to MAO-B, MAO-A has a higher specificity for serotonin and norepinephrine, while the two enzymes have similar affinity for dopamine and tyramine.[17]
MAO-A is a key regulator for normal brain function. In the brain, the highest levels of
Clinical significance
Cancer
MAO-A produces an amine oxidase, which is a class of enzyme known to affect carcinogenesis.
Cardiovascular disease
MAOA activity is linked to apoptosis and cardiac damage during cardiac injury following ischemic-reperfusion.[8]
Behavioral and neurological disorders
There is some association between low activity forms of the MAOA gene and
Depression
MAO-A levels in the brain as measured using positron emission tomography are elevated by an average of 34% in patients with major depressive disorder.[22] Genetic association studies examining the relationship between high-activity MAOA variants and depression have produced mixed results, with some studies linking the high-activity variants to major depression in females,[23] depressed suicide in males,[24] major depression and sleep disturbance in males[25] and major depressive disorder in both males and females.[26]
Other studies failed to find a significant relationship between high-activity variants of the MAOA gene and major depressive disorder.[27][28] In patients with major depressive disorder, those with MAOA G/T polymorphisms (rs6323) coding for the highest-activity form of the enzyme have a significantly lower magnitude of placebo response than those with other genotypes.[29]
Antisocial behavior
In humans, an association between the 2R allele of the VNTR region of the gene and an increase in the likelihood of committing serious crime or violence has been found. The VNTR 2R allele of MAOA has been found to be a risk factor for violent delinquency, when present in association with stresses, i.e. family issues, low popularity or failing school.[30][31][32][33]
A connection between the MAO-A gene 3R version and several types of anti-social behaviour has been found: Maltreated children with genes causing high levels of MAO-A were less likely to develop antisocial behavior.[34] Low MAO-A activity alleles which are overwhelmingly the 3R allele in combination with abuse experienced during childhood resulted in an increased risk of aggressive behaviour as an adult,[35] and men with the low activity MAOA allele were more genetically vulnerable even to punitive discipline as a predictor of antisocial behaviour.[36] High testosterone, maternal tobacco smoking during pregnancy, poor material living standards, dropping out of school, and low IQ predicted violent behavior are associated with men with the low-activity alleles.[37][38] According to a large meta-analysis in 2014, the 3R allele had a small, nonsignificant effect on aggression and antisocial behavior, in the absence of other interaction factors. Owing to methodological concerns, the authors do not view this as evidence in favor of an effect.[39]
The MAO-A gene was the first candidate gene for antisocial behavior and was identified during a "molecular genetic analysis of a large, multigenerational, and notoriously violent, Dutch kindred".[40] A study of Finnish prisoners revealed that a MAOA-L (low-activity) genotype, which contributes to low dopamine turnover rate, was associated with extremely violent behavior.[41] For the purpose of the study, "extremely violent behavior" was defined as at least ten committed homicides, attempted homicides or batteries.
However, a large genome-wide association study has failed to find any large or statistically significant effects of the MAOA gene on aggression.[42] A separate GWAS on antisocial personality disorder likewise did not report a significant effect of MAOA.[43] Another study, while finding effects from a candidate gene search, failed to find any evidence in a large GWAS.[41] A separate analysis of human and rat genome wide association studies, Mandelian randomization studies, and causal pathway analyses likewise failed to reveal robust evidence of MAOA in aggression.[44] This lack of replication is predicted from the known issues of candidate gene research, which can produce many substantial false positives.[45]
Aggression and the "Warrior gene"
Low-activity variants of the VNTR promoter region of the MAO-A gene have been referred to as the warrior gene.[46] When faced with social exclusion or ostracism, individuals with the low activity MAO-A variants showed higher levels of aggression than individuals with the high activity MAO-A gene.[47] Low activity MAO-A could significantly predict aggressive behaviour in a high provocation situation: Individuals with the low activity variant of the MAO-A gene were more likely (75% as opposed to 62%, out of a sample size of 70) to retaliate, and with greater force, as compared to those with a normal MAO-A variant if the perceived loss was large.[48]
The effects of MAOA genes on aggression have also been criticized for being heavily overstated.[49] Indeed, the MAOA gene, even in conjunction with childhood adversity, is known to have a very small effect.[50] The vast majority of people with the associated alleles have not committed any violent acts.[51][52]
Legal implications
In a 2009 criminal trial in the United States, an argument based on a combination of "warrior gene" and history of
Epigenetics
Studies have linked methylation of the MAOA gene with nicotine and alcohol dependence in women.[57] A second MAOA VNTR promoter, P2, influences epigenetic methylation and interacts with having experienced child abuse to influence antisocial personality disorder symptoms, only in women.[58] A study of 34 non-smoking men found that methylation of the gene may alter its expression in the brain.[59]
Animal studies
A dysfunctional MAOA gene has been correlated with increased aggression levels in mice,[60][61] and has been correlated with heightened levels of aggression in humans.[62] In mice, a dysfunctional MAOA gene is created through insertional mutagenesis (called 'Tg8').[60] Tg8 is a transgenic mouse strain that lacks functional MAO-A enzymatic activity. Mice that lacked a functional MAOA gene exhibited increased aggression towards intruder mice.[60][63]
Some types of aggression exhibited by these mice were territorial aggression, predatory aggression, and isolation-induced aggression.[61] The MAO-A deficient mice that exhibited increased isolation-induced aggression reveals that an MAO-A deficiency may also contribute to a disruption in social interactions.[64] There is research in both humans and mice to support that a nonsense point mutation in the eighth exon of the MAOA gene is responsible for impulsive aggressiveness due to a complete MAO-A deficiency.[60][62]
Interactions
Transcription factors
A number of
Inducers
Synthetic compounds that up-regulate the expression of MAO-A include
Inhibitors
Substances that inhibit the enzymatic activity of MAO-A include:
- Synthetic compounds
- Befloxatone (MD370503)
- Brofaromine (Consonar)
- Cimoxatone
- Clorgyline(irreversible)
- Methylene Blue
- Minaprine (Cantor)
- Moclobemide (Aurorix, Manerix)
- Phenelzine (Nardil)
- Pirlindole (Pirazidol)
- Toloxatone (Humoryl)
- Tyrima(CX 157)
- Tranylcypromine (nonselective and irreversible)
- Natural products
- Herbal sources
- Garlic (Garlic)
- Passion Flower, Tobacco smoke, Ayahuasca)
- Isoquinoline alkaloids
- Piperine (Black pepper)[66]
- Rosiridin[67] (in vitro)
See also
- Monoamine oxidase B
- Monoamine oxidase inhibitor - a class of antidepressant drugs that block or inactivate one or both MAO isoforms
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000189221 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025037 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 1678250.
- ^ PMID 2023912.
- ^ a b "Entrez Gene: MAOA monoamine oxidase A".
- ^ S2CID 21044944.
- PMID 22377710.
- S2CID 29954052.
- PMID 20505345.
- PMID 19005036.
- ^ PMID 21971000.
- ^ S2CID 52133633.
- ^ PMID 17573034.
- PMID 12015330.
- ^ PMID 32574581.
- PMID 14697906.
- PMID 22906985.
- S2CID 24366751.
- PMID 21039487.
- PMID 17088501.
- PMID 11121185.
- S2CID 19874514.
- S2CID 39844598.
- PMID 15956990.
- PMID 11992558.
- S2CID 30281258.
- S2CID 29200403.
- ^ Garcia-Arocena D. "The Genetics of Violent Behavior". The Jackson Laboratory. Retrieved 2021-03-23.
- PMID 18212819.
- S2CID 30271933.
- .
- S2CID 7882492.
- "Gene may protect abused kids against behavior problems". EurekAlert! (Press release). 2002-08-01.
- PMID 17534436.
- PMID 27014508.
- PMID 22297589.
- PMID 17429405.
- S2CID 11599122.
- PMID 24470068.
- ^ PMID 25349169.
- S2CID 13936647.
- PMID 27598967.
- PMID 29858598.
- S2CID 35033987.
- ^ Hogenboom M (28 October 2014). "Two genes linked with violent crime". BBC News. Retrieved 2014-11-01.
- S2CID 4830611.
- PMID 19168625.
- ^ Horgan J (26 April 2011). "Code rage: The "warrior gene" makes me mad! (Whether I have it or not)". Scientific American.
- ^ Hovet K (20 February 2018). "Chasing the 'warrior gene' and why it looks like a dud so far". Genetic Literacy Project.
- ^ Powledge TM (29 July 2016). "Do the MAOA and CDH13 'human warrior genes' make violent criminals—and what should society do?". Genetic Literacy Project.
- ^ "MAOA and CDH13 genes linked to violent crime, but can they explain criminal behavior?". Genetic Literacy Project. 29 October 2014.
- ^ Barber N (2010-07-13). "Pity the poor murderer, his genes made him do it". Psychology Today. Blog: "The Human Beast: Why we do what we do". Retrieved 2010-10-17.
- ^ Hagerty BB (2010-07-01). "Can Your Genes Make You Murder?". NPR.org. National Public Radio. Retrieved 2010-10-17.
- S2CID 235298342.
- PMID 27823806.
- PMID 18454435.
- PMID 21554924.
- PMID 22948232.
- ^ PMID 18418249.
- ^ PMID 17441000.
- ^ PMID 8211186.
- PMID 17441000.
- S2CID 33294633.
- PMID 21775495.
- PMID 15997146.
- PMID 19168123.
Further reading
- Rehan W, Sandnabba NK, Johansson A, Westberg L, Santtila P (October 2015). "Effects of MAOA genotype and childhood experiences of physical and emotional abuse on aggressive behavior in adulthood". Nordic Psychology. 67 (4): 301–12. S2CID 146577097.
- McDermott R, Tingley D, Cowden J, Frazzetto G, Johnson DD (February 2009). "Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation". Proceedings of the National Academy of Sciences of the United States of America. 106 (7): 2118–23. PMID 19168625.
- Edmondson DE, Binda C, Mattevi A (January 2004). "The FAD binding sites of human monoamine oxidases A and B". Neurotoxicology. 25 (1–2): 63–72. PMID 14697881.
- Craig IW (March 2007). "The importance of stress and genetic variation in human aggression". BioEssays. 29 (3): 227–36. S2CID 46059787.
External links
- Overview of all the structural information available in the PDB for UniProt: P21397 (Human Monoamine oxidase A) at the PDBe-KB.