Abstract
Aromatase excess syndrome (AEXS) is a rare autosomal dominant disorder characterized by gynecomastia. This condition is caused by overexpression of CYP19A1 encoding aromatase, and three types of cryptic genomic rearrangement around CYP19A1, that is, duplications, deletions, and inversions, have been identified in AEXS. Duplications appear to have caused CYP19A1 overexpression because of an increased number of physiological promoters, whereas deletions and inversions would have induced wide CYP19A1 expression due to the formation of chimeric genes consisting of a noncoding exon(s) of a neighboring gene and CYP19A1 coding exons. Genotype-phenotype analysis implies that phenotypic severity of AEXS is primarily determined by the expression pattern of CYP19A1 and 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.
Highlights
Aromatase encoded by CYP19A1 is a cytochrome P450 enzyme that plays a key role in estrogen biosynthesis [1]
Overexpression of CYP19A1 causes a rare autosomal dominant disorder referred to as aromatase excess syndrome (AEXS, OMIM no. 139300) [2,3,4,5,6,7,8]
Sequence analyses for the breakpoints have indicated that (1) inversion types are formed by a repeat sequence-mediated nonallelic intrachromosomal or interchromosomal recombination or by a replication-based mechanism of fork stalling and template switching (FoSTeS) that occurs in the absence of repeat sequences and is often associated with microhomology [16], (2) duplication type is generated by FoSTeS, and (3) deletions are produced by nonhomologous end joining that takes place between nonhomologous sequences and is frequently accompanied by an insertion of a short segment at the fusion point or by a nonallelic recombination [16]
Summary
Aromatase encoded by CYP19A1 is a cytochrome P450 enzyme that plays a key role in estrogen biosynthesis [1]. It catalyzes the conversion of Δ4-androstendione into estrone (E1) and that of testosterone (T) into estradiol (E2) in the placenta and ovary as well as in other tissues such as the fat, skin, bone, and brain [1]. CYP19A1 encoding aromatase is located on 15q21.2 adjacent to DMXL2 and GLDN (Figure 1) [3, 9]. It spans ∼123 kb and consists of at least 11 noncoding exons 1 and nine coding exons 2–10 [9,10,11,12]. Transcription of CYP19A1 appears to be tightly regulated by alternative usage of the multiple
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
