IA RI SCIARCGNTC

Misbehaving monoamine oxidase geneA nonsense mutation in the X-linked monoamine oxidase A gene

has been associated with sex-linked aggressive behaviour.

Genes encoding the enzymes of neurotransmittermetabolism are attractive candidates for involvement inpsychiatric disorders. Monoamine oxidase was the firstto be discovered of the enzymes that process pharma-cologically active amines [11, and it was soon recog-nized that the activities of monoamine oxidase towardsdifferent substrates varies between tissues. In mammals,this heterogeneity is due to the existence of two relatedtypes of flavin-containing enzyme, which can be distin-guished by their different substrate affinities andinhibitor specificities (see box) [2]. The two enzymeshave a wide variety of roles in the deamination ofdietary and neurotransmitter amines. Monoamineoxidase type A (MAOA) shows preferential activitytowards substrates such as serotonin and tryptamine,and it is typically the predominant form of the enzymein neural tissues (including the brain). Monoamineoxidase type B (MAOB) metabolizes dietary amines,including phenylethylamine which, although producedin small amount by the body, is particularly abundantin chocolate and has been shown to increase bloodpressure and glucose levels; very high levels ofphenylethylamine may trigger migraine attacks in sensi-tive individuals. The ability to inhibit selectively the Aand B forms of monoamine oxidase with a variety ofagents has greatly facilitated the elucidation of theirrespective biochemical roles, and these inhibitors havealso been used as drugs in the treatment of depressionand hypertension [3].

In addition to their role in the metabolism of endoge-nous and dietary amines, which might otherwise accu-mulate to toxic levels, monoamine oxidases areimportant in neurophysiology, serving to regulate thelevels of neurotransmitters released by neurons andthus the activity of synaptic pathways. In humans, up toa 50-fold variation in the activity levels of both A and Bforms of the enzyme has been detected between indi-viduals, and there is evidence that this is at least partlyunder genetic control. It might be thought remarkablethat enzymes with potentially vital roles in the metabo-lism of pharmacologically active amines should showsuch high levels of variation; however, it may be thatthe two forms of the enzyme are mutually complemen-tary, each covering for deficiencies in the other [4].Duplication of an ancestral gene may thus have pro-vided both built-in redundancy and an opportunity forseparate specialization of the two forms of monoamineoxidase. Nevertheless, given the important roles of theirproducts in modulating the levels of pharmacologicallyactive amines, the monoamine oxidase genes have longbeen considered good candidates for involvement ininherited abnormalities in behaviour.

A great deal of effort has therefore been expended inattempts to establish associations between monoamineoxidase activity levels and a wide range of behaviouraldisorders, such as schizophrenia, bipolar affected disorder,alcoholism and stimulus-seeking personality. Statisticallysignificant associations have been found between lowMAOB activity levels and all of these disorders apart fromschizophrenia, for which the data are conflicting. Therehas always been the perception, however, that MAOB isless likely than MAOA, the main neural form of theenzyme, to be causally involved in major atypical behav-iour syndromes. Measurements of activity levels of themore promising MAOA have, however, been difficult.Reliable MAOA assays have required the isolation andculture of fibroblasts; for this reason, only a few studieshave been attempted and these have generally beeninconclusive [4].

The search for associations between behavioural abnor-malities and defects of monoamine oxidase genes haverecently been dramatically advanced by studies of aremarkable Dutch pedigree, and in this case MAOAappears to be the culprit. Several males in this familyexhibit borderline mental retardation associated withimpulsive aggression and inappropriate behaviour inducedby stress, the manifestations of which include arson, rapeand voyeurism. Initial genetic studies [5] showed the traitis X linked: it co-segregates with a dinucleotide repeat at

Fig. 1. Segregation of the MAOA nonsense mutation in part ofthe Dutch pedigree showing an X-linked behavioural disorder. Allaffected males and obligate carrier females have a C to T mutationthat changes codon 296 from CAG, for glutamine, to TAG, atranslational termination codon; in twelve normal males, onlythe normal C is present. (Adapted from 191.)

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of the three tested showed elevated excretion of MAOAsubstrates and reduced excretion of expected MAOAproducts.

These clues were rapidly followed up by studies of MAOAexpression in fibroblast cultures and by direct sequencingof MAOA cDNAs from affected and normal familymembers [61. Negligible levels of MAOA activity weredetected in samples from the three affected males thatwere assayed, in contrast to the normal levels in samplesfrom carrier females and controls. Sequencing revealed, inaddition to three conservative base substitutions thought torepresent neutral polymorphisms, a nonsense mutation -changing the codon CAG, which encodes residue gluta-mine 296, to TAG - in cDNAs from five affected malesand two carrier females, but not in cDNAs from any oftwelve non-affected male members of the pedigree(Fig. 1).

The inescapable conclusion is that affected males in thepedigree are incapable of producing normal MAOAenzyme and, as a consequence, suffer from profoundlydisturbed monoamine neurotransmitter metabolism. It isimportant to note, however, that the associated behav-ioural manifestations are quite variable with aggressiveepisodes, in particular, fluctuating markedly in severityand over time. MAOA inhibitors have been widelyemployed clinically with no evidence of increased aggres-sive tendencies as a side-effect [31. The implication is thatpartial deficiencies in monoamine oxidase activities can beaccommodated, perhaps because they are compensatedfor by the activities of related enzymes, but that total, life-long lack of MAOA activity, as in affected males of theDutch pedigree, has profound behavioural consequences.

Surprisingly, a number of cases have been described pre-viously of males completely lacking either MAOA alone orboth MAOA and MAOB. In these unfortunate individuals,however, the deficiencies are just one part of a moreextensive deletion, involving loss of other genes includingthe Norrie disease gene (see box). Their clinical conditionis thus difficult to distinguish from the pattern of abnormalfeatures shown by individuals with mutations affectingonly the Norrie disease gene, and the consequences ofloss of sight complicate the evaluation of any additionalbehavioural disturbance that may be associated with theloss of MAOA and MAOB activities.

the MAOA locus and was mapped genetically to Xp21-pll, the proximal part of the short arm of the X chromo-some; obligate female carriers are unaffected. Monoamineoxidases regulate the levels of serotonin, dopamine andnoradrenaline, abnormalities in the metabolism of all ofwhich have been associated with aggressive tendencies.Affected males of the Dutch pedigree were thereforetested for changes in levels of amine metabolites, and all

These observations have profound implications and raisesimilar issues to those that led to the controversy over thereports [71 of increased aggressive and criminal behaviourin some XYY males. A search for other cases of abnormalMAOA activity associated with behavioural disorders is apriority. It is possible that these new results on the Dutchpedigree may lead to monoamine oxidase deficienciesbeing implicated in other atypical behavioural disorders.Nevertheless, in the case of profound disorders it seemsunlikely that such associations would have gone unno-ticed, given the rather obvious nature of sex-linked inheri-tance, and the almost routine monitoring of aminemetabolites in clinically disturbed individuals. It is muchmore likely that cryptic variations in monoamine oxidase

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levels will turn out to account for behavioural patternsregarded as within the normal range; if so, difficult ethicaland practical questions will be raised.

When the role of the Y chromosome in mammalian testisdetermination was established, it was assumed that one, orvery few, Y chromosome genes provide the trigger formaleness. Apart from the X-linked androgen receptorgene, a deficiency of which causes testicular feminization,the involvement of other X and Y genes in sexual behav-iour was unexpected. The identification of the MAOAlocus as a behavioural determinant follows soon afterthe publication of evidence that implicates a locus on theX chromosome in the sexual orientation of some homo-sexuals [8]. The sex chromosomes may be even moreappropriately named than at first realized.

References1. HARE MLC: Tyramine oxidase, a new enzyme system in the liver.

BiochemJ 1928, 22:968-979.2. FOWLER CJ, CAI.LINGHAM BA, MANTLE TF, TIPTON KF: Monoamine

oxidase A and B: a useful concept. Btochem Pharmacol 1978,27:97-101.

3. Monoamine Oxtdase: Its role in normal and disease states. Editedby Lieberman A, Olanow CW, Youdim M, Tipton KF. New York:Marcel Dekker, Inc; 1993.

4. BREAKEFIEI.D XO, CHEN Z-Y, TIVOL E, SHALISH C, CRAIG IW:Molecular genetics and inheritance of human MAO-A and MAO-B.In: Monoamine Oxidase: Its role in normal and disease states.Edited by Lieberman A, Olanow CW, Youdim M, Tipton KF.New York: Marcel Dekker, Inc; 1993.

5. BRUINNER HG, NELEN MR, VAN ZANDVOORT P, ABELING NGGM, VANGENNIP AH, WOLTERS EC, KUIPER MA, ROPERS HH, VAN OosT BA: X-linked borderline mental retardation with prominent behavioraldisturbance: phenotype, genetic localisation, and evidence fordisturbed monoamine metabolism. Am J Hum Genet 1993,52:1032-1039.

6. BRUNNER HG, NELEN MR, BREAKEFIELD XO, ROPERS HH, VAN OoSTBA: Abnormal behaviour associated with a point mutation in thestructural gene for monoamine oxidase A. Science 1993,262:578-580.

7. HOOK EB: Behavioural implications of the human XYY genotype.Science 1973, 179:139-149.

8. HAMER DH, HU S, MAGNUSON VL, Hu N, PATTATUCCI AML: Alinkage between DNA markers on the X chromosome and malesexual orientation. Science 1993, 261:321-327.

9. CHEN Z-Y, POWELL JF, Hsu Y-P, BREAKEFIEI.D, CRAIG W: The organi-sation of the human monoamine oxidase genes and the longrange physical mapping around them. Genomics 1992, 14:75-82.

10. CHEN Z-Y, HENDRICKS RW, JOBLING MA, POWELL JF, BReAKEFIELDXO, DAVIES KE, CRAIG IW: Isolation and characterisation of a geneimplicated in Norrie disease, Nature Genet 1992, 1:204-208.

Ian Craig, Genetics Laboratory, Department ofBiochemistry, South Parks Road, Oxford, OX1 3QU, UK.

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