Molecular Bases and Phenotypic Determinants of Aromatase Excess Syndrome

Abstract

Aromatase excess syndrome (AEXS) is a rare autosomal dominant disorder characterized by gynecomastia. This condition is caused by overexpression ofCYP19A1encoding aromatase, and three types of cryptic genomic rearrangement aroundCYP19A1, that is, duplications, deletions, and inversions, have been identified in AEXS. Duplications appear to have causedCYP19A1overexpression because of an increased number of physiological promoters, whereas deletions and inversions would have induced wideCYP19A1expression due to the formation of chimeric genes consisting of a noncoding exon(s) of a neighboring gene andCYP19A1coding exons. Genotype-phenotype analysis implies that phenotypic severity of AEXS is primarily determined by the expression pattern ofCYP19A1and the chimeric genes and by the structural property of the fused exons with a promoter function (i.e., the presence or the absence of a natural translation start codon). These results provide novel information about molecular mechanisms of human genetic disorders and biological function of estrogens.