Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene.
BACKGROUND
Gynecomastia of prepubertal onset may result from increased estrogen owing to excessive aromatase activity in extraglandular tissues. A gene in chromosome 15q21.2 encodes aromatase, the key enzyme for estrogen biosynthesis. Several physiologic tissue-specific promoters regulate the expression of aromatase, giving rise to messenger RNA (mRNA) species with an identical coding region but tissue-specific 5'-untranslated regions in placenta, gonads, brain, fat, and skin.


METHODS
We studied skin, fat, and blood samples from a 36-year-old man, his 7-year-old son, and an unrelated 17-year-old boy with severe gynecomastia of prepubertal onset and hypogonadotropic hypogonadism caused by elevated estrogen levels.


RESULTS
Aromatase activity and mRNA levels in fat and skin and whole-body aromatization of androstenedione were severely elevated. Treatment with an aromatase inhibitor decreased serum estrogen levels and normalized gonadotropin and testosterone levels. The 5'-untranslated regions of aromatase mRNA contained the same sequence (FLJ) in the father and son and another sequence (TMOD3) in the unrelated boy; neither sequence was found in control subjects. These 5'-untranslated regions normally make up the first exons of two ubiquitously expressed genes clustered in chromosome 15q21.2-3 in the following order (from telomere to centromere): FLJ, TMOD3, and aromatase. The aromatase gene is normally transcribed in the direction opposite to that of TMOD3 and FLJ. Two distinct heterozygous inversions reversed the direction of the TMOD3 or FLJ promoter in the patients.


CONCLUSIONS
Heterozygous inversions in chromosome 15q21.2-3, which caused the coding region of the aromatase gene to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, resulted in severe estrogen excess owing to the overexpression of aromatase in many tissues.
Shozu
Makio
M
Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, USA.
Sebastian
Siby
S
Takayama
Kazuto
K
Hsu
Wei-Tong
WT
Schultz
Roger A
RA
Neely
Kirk
K
Bryant
Michael
M
Bulun
Serdar E
SE
D000273:Adipose Tissue / Q000201:enzymology; D000293:Adolescent; D000328:Adult; D000077384:Anastrozole; D000735:Androstenedione / Q000097:blood / Q000378:metabolism; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D047072:Aromatase Inhibitors; D001483:Base Sequence; D002648:Child; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000097:blood*; D004970:Estrone / Q000097:blood*; D005347:Fibroblasts / Q000201:enzymology; D005938:Glucocorticoids / Q000494:pharmacology; D006177:Gynecomastia / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D014230:Triazoles / Q000494:pharmacology
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D009570:Nitriles; D012333:RNA, Messenger; D014230:Triazoles; D004970:Estrone; D000077384:Anastrozole; D000735:Androstenedione; D004958:Estradiol; D003907:Dexamethasone; D001141:Aromatase