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MAO-A Gene Determines Levels of Enzyme Activity

Three Distinct Versions of the MAO-A Gene and their Correlation to Enzyme Activity

In a 1991 experiment by Hotamisligil and Breakefield, the MAO-A gene was obtained from many subjects and analyzed for mutations that have been reported previously in the literature, and the variations in DNA structure were then statistically analyzed for correlation with MAO-A activity.

Three known mutations were examined. One occurred at position 941, a guanine substituted for a thymine. This mutation created an extra cleavage point for the enzyme Fnu4HI (a restriction endonuclease). A mutation at position 1460 consisted of a thymine instead of a cytosine. This creates a new restriction site (cleavage point) for the enzyme EcoRV. Both of these mutations occur in the third base of a codon(sequence of three bases coding for a particular amino acid) and they do not affect the enzyme amino acid sequence (due to a silent mutation as a result of the fact that some amino acids have more than one codon). The third mutation analyzed was on the non-coding portion of the gene, thought to be involved in regulatory functions. The mutation was a "restriction fragment length polymorphism" and was labeled MspI.

By looking for these three mutations, the researchers were able to look for up to 8 distinct MAO-A genes, although they only found three of the possible alleles(traits). Hotamisligil and Breakefield tested their 40 male subjects for each of these mutations, determining which allele was carried by each person. 27 of the 40 subjects had no mutations, 3 had only the MspI mutation, and 10 had all three mutations.

These different alleles were then statistically analyzed for correlation with MAO-A activity levels. It was found the that both of the mutated alleles were significantly correlated to high levels of MOA-A activity, and the normal allele was correlated to lower MAO-A levels. The strong correlation between differences in MAO-A alleles and differences in MAO-A enzyme activity seems to suggest that these polymorphism are indicators of structural differences in portions of the MAO-A gene that regulate gene expression.

These findings also have behavioral and clinical applications. The Bipolar disorder is often thought of as a mostly genetic disorder, and a recent experiment has supported that hypothesis. Three alleles in the MAO-A gene (including MspI) and one allele from MAO-B were analyzed in a control group and in a group of bipolar patients. A significant correlation was found between all three MAO-A alleles and bipolar disorder. The MAO-B allele had no correlation with bipolar disorder. This evidence seems to suggest the bipolar patients have below-normal MAO-A activity levels. Of course, this experiment isn't telling us that the MAO-A gene is the "bipolar gene". It just gives us a framework to predict with. We now know that certain alleles on the MAO-A gene have the ability to decrease enzyme activity, which can lead to increased susceptability to bipolar disorder.