Estrogen Excess Associated with Novel Gain-of-Function Mutations Affecting the Aromatase Gene
Makio Shozu, M.D., Ph.D., Siby Sebastian, Ph.D., Kazuto Takayama, M.D., Ph.D., Wei-Tong Hsu, M.D., Roger A. Schultz, Ph.D., Kirk Neely, M.D., Michael Bryant, M.D., and Serdar E. Bulun, M.D.
Background Gynecomastia of prepubertal onset may result fromincreased estrogen owing to excessive aromatase activity inextraglandular tissues. A gene in chromosome 15q21.2 encodesaromatase, the key enzyme for estrogen biosynthesis. Severalphysiologic tissue-specific promoters regulate the expressionof aromatase, giving rise to messenger RNA (mRNA) species withan identical coding region but tissue-specific 5'-untranslatedregions in placenta, gonads, brain, fat, and skin.
Methods We studied skin, fat, and blood samples from a 36-year-oldman, his 7-year-old son, and an unrelated 17-year-old boy withsevere gynecomastia of prepubertal onset and hypogonadotropichypogonadism caused by elevated estrogen levels.
Results Aromatase activity and mRNA levels in fat and skin andwhole-body aromatization of androstenedione were severely elevated.Treatment with an aromatase inhibitor decreased serum estrogenlevels and normalized gonadotropin and testosterone levels.The 5'-untranslated regions of aromatase mRNA contained thesame sequence (FLJ) in the father and son and another sequence(TMOD3) in the unrelated boy; neither sequence was found incontrol subjects. These 5'-untranslated regions normally makeup the first exons of two ubiquitously expressed genes clusteredin chromosome 15q21.2–3 in the following order (from telomereto centromere): FLJ, TMOD3, and aromatase. The aromatase geneis normally transcribed in the direction opposite to that ofTMOD3 and FLJ. Two distinct heterozygous inversions reversedthe 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 lieadjacent to constitutively active cryptic promoters that normallytranscribe other genes, resulted in severe estrogen excess owingto the overexpression of aromatase in many tissues.
Source Information
From the Departments of Obstetrics and Gynecology and Molecular Genetics, University of Illinois at Chicago, Chicago (M.S., S.S., S.E.B.); the Department of Obstetrics and Gynecology, Kanazawa University, Kanazawa, Japan (M.S.); the Department of Obstetrics and Gynecology, Tohoku University, Sendai, Japan (K.T.); the Department of Pediatrics, Rush Medical School, Chicago (W.-T.H.); the Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas (R.A.S.); the Department of Pediatrics, Stanford University, Palo Alto, Calif. (K.N.); and the Department of Pediatrics, Children's Hospital, Los Angeles (M.B.). Drs. Shozu and Sebastian contributed equally to the article.
Address reprint requests to Dr. Bulun at the Department of Obstetrics and Gynecology, Northwestern University Medical School, 333 E. Superior, Suite 490, Chicago, IL 60611, or at s-bulun{at}northwestern.edu.
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