Association between monoamine oxidase A activity in human male skin fibroblasts and genotype of the MAOA promoter-associated variable number tandem repeat

Abstract

Among fifteen male skin fibroblast cultures from eleven donors ranging in age from less than 1 year to 90 years old, the specific activity of monoamine oxidase A (MAO-A) differed 515-fold. Each culture had one of the two most common alleles (three or four 30-bp repeats) at the variable number tandem repeat locus positioned 1.2 kb upstream from MAOA exon 1 (uVNTR). The mean MAO-A activity in cultures with three uVNTR repeats was significantly lower than that in cultures with four repeats (1.6 +/- 1.1 and 13 +/- 12 nmol/h per milligram, respectively; P=0.032). MAO-A expression was confined to a cell sub-population varying from 0.5% to 90% of cells in different cultures. The mean specific activity in MAO-A+ cells (whole culture specific activity divided by the proportion of immunopositive cells) was lower for cultures with three repeats than for those with four (7.2 +/- 3.1 and 23.9 +/- 9.5 nmol/h per milligram protein, respectively; P=0.0013), with no overlap in activity between genotypes. Finding lower MAO-A activity in cultures with three uVNTR repeats compared to those with four is consistent with published evidence that MAO-A promoter constructs bearing three repeats have lower transcriptional activity in transfected neuroblastoma and choriocarcinoma cells. The uVNTR genotype may be a common genetic determinant of significant individual differences in oxidizing capacity for critical MAO-A substrates, which include serotonin, norepinephrine, and tyramine.

A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index

“…48 However, a locus affecting transcription of one gene might affect the other, although this possibility is speculative. Although a functional effect of MAOA-LPR has been demonstrated in cell lines 12,14 and human fibroblasts, 13 its effect on MAOA mRNA and MAOA protein levels in human post-mortem brain tissue appears to be very weak and insignificant. 49 In the Balciuniene et al 40 study, a haplotype composed of the low activity MAOA-LPR 3 repeat allele and a SNP from an intronic region in MAOB was significantly associated with decreased MAOA function, whereas other MAOA-LPR/MAOB SNP haplotypes containing the MAOA-LPR 3 repeat allele were associated with higher expression.…”

“…Studies in both humans and non-human animal models have supported the involvement of MAOA in the etiology of externalizing behaviors, including impulsivity and aggression and several psychiatric disorders in which these behaviors play a role, including antisocial personality disorder (ASPD), conduct disorder (CD), attention deficit hyperactivity disorder (ADHD), and alcoholism [4][5][6][7][8][9][10] In 1993, Brunner et al 4,11 reported a Dutch family in which eight males were affected by a syndrome characterized by borderline mental retardation and impulsive behavior including impulsive aggression, arson, attempted rape, fighting, and exhibitionism The syndrome was due to a stop-codon variant in the eighth exon of MAOA leading to complete and selective deficiency of MAOA activity. This stopcodon variant has not been observed in other study populations; however, subsequent efforts led to the discovery of a common MAOA polymorphism that was shown to affect transcriptional activity [12][13][14] and that is generally assumed to result in a deficiency of MAOA in vivo. This locus, termed 'MAOA linked polymorphic region' (MAOA-LPR or MAOA-uVNTR), is a variable number of tandem repeats (VNTR) located in the gene's transcriptional control region, approximately 1.2 kb upstream of the start codon.…”

MAO A VNTR polymorphism and amygdala volume in healthy subjects

“…Catabolism of 5-HT is regulated by the activity of the monoamine oxidase (MAO) enzyme, with the isoform MAO A having a much greater affinity for the substrate than the isoform MAO B (Shih and Chen, 1999). The MAO A coding gene (Xp11.4-Xp11.3) presents a well-characterized functional polymorphism consisting of a variable number of tandem repeats (VNTR) in the promoter region with different length variants that selectively influence the protein transcription and, hence, the enzymatic activity (Denney et al, 1999). Enzyme expression is relatively high for carriers of 3.5 or 4 repeats (MAO A High) and is lower for carriers of 2, 3 or 5 repeats (MAO A Low) (Sabol et al, 1988).…”

Cluster B Personality Disorders are Associated with Allelic Variation of Monoamine Oxidase A Activity

“…Functional studies revealed that the MAOA-LPR modulates transcriptional activity of MAOA and ultimately enzyme activity (Sabol et al, 1998;Deckert et al, 1999;Denney et al, 1999). It may also influence CSF 5-HIAA concentrations gender-specifically in women (Jonsson et al, 2000).…”