Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: CYP19A1
SNOMEDCT: 427627006, 709075008;
Cytogenetic location: 15q21.2 Genomic coordinates (GRCh38): 15:51,208,057-51,338,596 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.2 | Aromatase deficiency | 613546 | 3 | |
| Aromatase excess syndrome | 139300 | Autosomal dominant | 3 |
Aromatase (EC 1.14.14.1), also called estrogen synthetase, is a member of the cytochrome P450 superfamily. The enzyme catalyzes the conversion of androgen to estrogen, a rate-limiting step in estrogen biosynthesis (Harada et al., 1992).
In reviewing the regulation of expression of P450 genes, Whitlock (1986) discussed P450-aromatase, which is induced by follicle-stimulating hormone (FSH; see 136530) via formation of cyclic AMP. Presumably the increased activity reflects increased transcription of the P450-aromatase gene. Aromatase is present in many tissues including skin, muscle, fat, and nerve, where it may contribute to sex-specific differences in cellular metabolism.
Chen et al. (1986) and Evans et al. (1986) cloned and sequenced partial human placental cDNAs corresponding to the aromatase gene. Evans et al. (1986) found that the radiolabeled aromatase cDNA hybridized to several size species of mRNA in both placental and adipose stromal cell RNA fractions.
Harada (1988) isolated a complete cDNA clone encoding human aromatase from a placenta cDNA library. A study of the deduced 503-amino acid sequence and a comparison with other forms of cytochrome P450 indicated that this enzyme is a unique member of the cytochrome P450 superfamily.
Corbin et al. (1988) also cloned a full-length human cDNA for P450-aromatase encoding a deduced 503-amino acid protein with striking similarity to other members of the cytochrome P450 gene superfamily. Corbin et al. (1988) expressed the cDNA in COS-1 monkey kidney tumor cells and found that the expressed protein was similar in size to human placental aromatase, as detected by immunoblot analysis, and catalyzed the aromatization of all 3 major physiologic substrates: androstenedione, testosterone, and 16-alpha-hydroxyandrostenedione. The activity was inhibited by known aromatase inhibitors.
Toda et al. (1990) found that the CYP19 gene spans at least 70 kb of genomic DNA and contains 10 exons. The translational initiation site and the termination site are located in exon 2 and exon 10, respectively.
By analysis of overlapping BAC clones identified by homology searching of public databases, Sebastian and Bulun (2001) determined the organization of the CYP19 gene. Their analysis shows that the entire gene spans more than 123 kb of DNA. Only the 30-kb 3-prime region encodes aromatase, whereas a large 93-kb 5-prime flanking region serves as the regulatory unit of the gene. The most proximal promoters, the ovarian-specific promoter II and 2 other proximal promoters, I.3 (expressed in adipose tissue and breast cancer) and I.6 (expressed in bone), are located within 1 kb of the translation start site.
Sebastian et al. (2002) stated that the CYP19 gene contains 9 alternative untranslated first exons, each with an individual promoter. They identified a tenth alternative first exon, exon I.7. Exon I.7 contains no TATA or CAAT boxes, but it has 2 consensus GATA (see GATA1; 305371) motifs and other cis-acting motifs.
Sparkes et al. (1987) used the CYP19 cDNA identified by Chen et al. (1986) in the study of human/mouse somatic cell hybrids for assignment of the gene to human chromosome 15. By in situ hybridization, Chen et al. (1988) mapped the ARO gene to 15q21.1.
Using data from the Human Genome Project and screening a BAC plasmid library, Shozu et al. (2003) mapped the CGNL1 gene (607856), the tropomodulin-3 gene (TMOD3; 605112), and the aromatase gene, in that order from telomere to centromere, to 15q21.1-q21.3. They found that the aromatase gene is normally transcribed in the direction opposite to that of TMOD3 and CGNL1.
Aromatase is located in the ovary and placenta and participates in the regulation of reproductive functions. The enzyme is also widely distributed in extragonadal tissues such as muscle, liver, hair follicles, adipose tissue, and brain. This finding suggests that estrogen produced by this enzyme has physiologic functions not only as a sex steroid hormone but also in growth or differentiation (summary by Harada et al., 1992).
Zhou et al. (1991) studied structure-function relationships in human aromatase using site-directed mutagenesis and a stable expression system that involved a plasmid containing human placenta aromatase cDNA in Chinese hamster ovary (CHO) cells. A phe406-to-arg mutant was completely inactive. Only small changes in enzyme kinetics occurred with mutants tyr361 to phe and tyr361 to leu, leading to the conclusion that tyr361 is not directly involved in substrate binding. The mutant pro308 to phe had altered catalytic properties, suggesting that pro308 is situated in the active site of the enzyme.
Biosynthesis of estrogens from C19 steroids is catalyzed by aromatase and its tissue-specific expression is determined at least in part by alternative use of tissue-specific promoters, which give rise to transcripts with unique 5-prime noncoding termini. The distal promoter (I.1) is responsible for expression uniquely in the placenta, while the proximal promoter (II), which regulates expression via a cAMP-dependent signaling pathway, is responsible for expression in the gonads. Transcripts in breast adipose tissue contain 5-prime termini corresponding to expression derived from use of promoters I.4 predominantly as well as II and I.3. Promoter I.4 contains a glucocorticoid response element and an interferon-gamma activation site element, and is responsible for expression in the presence of glucocorticoids and members of the class I cytokine family. Agarwal et al. (1997) determined the distribution of these various transcripts in adipose tissue from abdomen, buttocks, and thighs of women to characterize the factors regulating aromatase expression in these sites. They used competitive RT-PCR to amplify unique 5-prime ends of each of the transcripts of the CYP19 gene expressed and the coding region to evaluate total transcript levels in adipose tissue. They found that exon I.4-specific transcripts were predominant in adipose tissue obtained from women regardless of the tissue site or the age of the individual. They also found that transcript levels increased in direct proportion to advancing age and were the highest in buttocks, followed by thighs, and lowest in abdomen adipose tissue. Thus it appears that in normal human adipose tissue, aromatase expression is mainly under local control by a number of cytokines via paracrine and autocrine mechanisms in the presence of systemic glucocorticoids.
The distinct gender-specific patterns of fat distribution in men and women (android and gynoid) suggest a role for sex steroids. It has been suggested that estrogens can promote preadipocyte cell proliferation and/or differentiation. The enzyme CYP19 is responsible for the conversion of androgen precursor steroids to estrogens and may, therefore, have a role in regulating adipose tissue mass and its distribution. McTernan et al. (2002) investigated the glucocorticoid regulation of aromatase expression in adipose tissue, specifically to define any site- and gender-specific differences. Abdominal subcutaneous and omental adipose tissue was obtained from male and female patients undergoing elective surgery. Cortisol-induced aromatase activity in omental adipocytes from postmenopausal females was higher than that in premenopausal females (P less than 0.001). Insulin had no independent effect on aromatase expression, but coincubation of preadipocytes with cortisol and insulin eliminated both gender- and site-specific differences. The authors concluded that in women, but not men, cortisol increases aromatase activity at subcutaneous sites, and this may facilitate predilection for subcutaneous adiposity in females. They suggested that the observed site-, gender-, and menopausal-specific differences in the glucocorticoid regulation of this enzyme may contribute to the gender- and menopausal-specific patterns of fat distribution.
By standards of other CYP genes, CYP19 is extraordinarily large (more than 50 kb). The large size of the gene is probably related to the transcription of CYP19 in different cell types under the regulation of different promoters. Simpson et al. (1997) summarized their findings of several distinct CYP19 promoters with alternative splicing which leads to the production of the same enzyme in all cells. Numerous untranslated first exons occur in aromatase transcripts in a tissue-specific fashion due to differential splicing as a consequence of the use of tissue-specific promoters. Thus, expression in the ovary uses a proximal promoter that is regulated primarily by cAMP. On the other hand, expression in the placenta uses a distal promoter located at least 40 kb upstream of the start of transcription that is regulated by retinoids. Other promoters are used in brain and adipose tissue. In the latter case, class I cytokines such as IL6 (147620) and IL11 (147681), as well as TNF-alpha (TNFA; 191160), are important regulatory factors. A common 3-prime splice junction located upstream of the start of translation is used in all of the splicing events involved in the use of these various promoters. Thus, the coding region of the transcripts, and hence the protein, are identical regardless of the tissue site of expression; what differs in a tissue-specific fashion is the 5-prime end of the transcripts. This pattern of expression has great significance both from a phylogenetic and ontogenetic standpoint, as well as for the physiology and pathophysiology of estrogen formation.
Wang et al. (2001) presented the results of in vivo and in vitro analyses indicating that aromatase is a physiologic target of DAX1 (NR0B1; 300473) in Leydig cells, and that increased aromatase expression may account, in part, for the infertility and Leydig cell hyperplasia in Dax1-deficient mice.
Aquila et al. (2002) noted that testicular expression of CYP19 has been shown in both somatic and germ cell types in several species, whereas in humans, testicular expression is confined to the somatic cells. They investigated whether CYP19 is present in human ejaculated spermatozoa. Using RT-PCR and specific primers, they amplified the highly conserved helical, aromatic, and heme-binding sequences of the conventional human CYP19 from RNA isolated from human spermatozoa. Employing a rabbit polyclonal antiserum directed against human placental CYP19, immunoblotting analysis demonstrated aromatase protein expression, which was localized primarily to the tail and midpiece of spermatozoa. Aquila et al. (2002) concluded that human spermatozoa are a potential site of estrogen biosynthesis.
Using RT-PCR and semiquantitative RT-PCR, Sebastian et al. (2002) found that CYP19 variants containing exon I.7, an alternative untranslated first exon, were highly expressed in some subcutaneous adipose tissue samples, but not in normal breast adipose tissue or any other normal tissue examined. Exon I.7-containing CYP19 was highly expressed in breast cancer tissue and in breast adipose tissue adjacent to cancer.
Sebastian et al. (2002) determined that the 2 consensus GATA sites within the promoter region of alternative exon I.7 were critical for basal CYP19 promoter activity in human microvascular endothelial cells. GATA2 (137295), but not GATA1, bound the GATA sites and activated expression of a reporter gene in a concentration-dependent manner.
In human endometriotic stromal cells, markedly high levels of CYP19 mRNA and promoter II activity are present and can be vigorously stimulated by prostaglandin-E2 via a cAMP-dependent pathway to give rise to physiologically significant estrogen biosynthesis. Yang et al. (2002) evaluated the possible roles of C/EBP isoforms in the regulation of P450-aromatase expression in endometriotic versus eutopic endometrial stromal cells. They disrupted several potential sequences and found that mutations of a -211/-197-bp cAMP-response element (CRE) and a -317/-304-bp C/EBP binding site abolished both baseline and cAMP-induced promoter II activity. The authors concluded that both -317/-304 and -211/-197-bp elements in promoter II are critical for the robust cAMP-dependent induction in endometriosis. C/EBP-alpha upregulates, whereas C/EBP-beta and C/EBP-delta inhibit, P450-aromatase promoter activity via binding primarily to the -211/-197-bp CRE under in vitro conditions. In vivo downregulation of C/EBP-beta in endometriotic stromal cells and its upregulation in endometrial stromal cells may in part account for the induction of CYP19 expression in endometriosis and its inhibition in endometrium.
Shozu et al. (2002) noted that the CYP19 gene is expressed in several extragonadal sites and regulated in a tissue-specific fashion, which is achieved by alternative use of the 7 different promoters, and corresponding exons 1, of the CYP19 gene. To elucidate the mechanism by which aromatase P450 is overexpressed in leiomyomas, they sought to determine the promoter used for aromatase P450 expression in leiomyomas. By 5-prime-RACE analysis Shozu et al. (2002) revealed that of 6 leiomyoma nodules tested, 4 contained I.4-specific transcript of aromatase P450 alone, 1 contained PII-specific transcript alone, and the remaining nodule contained both I.4- and PII-specific transcripts simultaneously. The transcriptional ability of the promoter I.4 sequence was confirmed by transient transfection assay using primary cells released from leiomyomas and established cells from normal myometrium (KW cells). Luciferase vectors containing promoter I.4 sequence (-340/+14 or longer) showed a significant increase in luciferase activity in response to dexamethasone. Deletion or mutation of a putative glucocorticoid-responsive element in the promoter I.4 sequence eliminated promoter activity. The authors concluded that promoter I.4 is the major promoter responsible for overexpression of aromatase P450 in leiomyomas and that a glucocorticoid-responsive element within it plays a substantial role in the expression of aromatase P450.
Imir et al. (2007) reported that aromatase expression is regulated via the alternatively used promoters in the placenta (I.1 and I.2a), fat (I.4, I.3, and II), bone (I.6), and gonads (II). A prostaglandin E2/cAMP-dependent pathway regulates coordinately the proximal promoters I.3/II, whereas glucocorticoids and cytokines regulate the distal promoter I.4. They demonstrated that aromatase expression in leiomyoma tissue in vivo is primarily regulated by the promoter I.3/II region rather than I.4.
Ishikawa et al. (2008) demonstrated that cAMP-induced binding of CEBP-beta (189965) to multiple motifs in the CYP19 promoter I.3/II region is a critical mechanism regulating aromatase expression in leiomyoma smooth muscle cells in primary culture. The authors concluded that definition of this mechanism further may assist in designing inhibitors of aromatase specific for leiomyoma tissue.
Parakh et al. (2006) found that expression of beta-catenin (CTNNB1; 116806) lacking the N-terminal 90-amino acids that lead to its degradation significantly enhanced FSH-mediated induction of CYP19A1 and CYP11A1 (118485) mRNA. CYP19A1 transactivation by SF1 (601516) required a functional interaction with beta-catenin and an intact beta-catenin-binding site. The beta-catenin-binding site was also critical for the synergistic actions of FSH and SF1 on CYP19A1. The actions of beta-catenin on CYP19A1 were dependent on hormone-induced cAMP cascades. Parakh et al. (2006) concluded that beta-catenin is essential for FSH/cAMP-regulated gene expression in ovary and that beta-catenin has a role in estrogen biosynthesis.
Diaz-Cruz et al. (2005) studied the effects of nonsteroidal antiinflammatory drugs and COX1 (176805)- and COX2 (600262)-selective inhibitors on aromatase activity and expression in human breast cancer cells. The data from these experiments revealed dose-dependent decreases in aromatase activity after treatment with all agents. Real-time PCR analysis of aromatase gene expression showed a significant decrease in mRNA levels when compared with control for all agents. These results were consistent with enzyme activity data, suggesting that the effect of COX inhibitors on aromatase begins at the transcriptional level. Exon-specific real-time PCR studies suggested that promoters I.3, I.4, and II are involved in this process.
Crystal Structure
Ghosh et al. (2009) presented the crystal structure of human placental aromatase, the only natural mammalian full-length P450, and the first P450 in hormone biosynthetic pathways to be crystallized. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. Ghosh et al. (2009) suggested that the molecular basis for the enzyme's androgenic specificity and unique catalytic mechanisms can be used for developing next-generation aromatase inhibitors.
Aromatase Deficiency
In an 18-year-old 46,XX female with aromatase deficiency (613546), Ito et al. (1993) described compound heterozygosity for 2 mutations in the CYP19A1 gene (107910.0001-107910.0002). They indicated that this was the first definitive case of an adult with aromatase deficiency to be reported.
Harada et al. (1992) demonstrated that the aromatase deficiency in the case reported by Shozu et al. (1991) was caused by the expression of an abnormal aromatase protein molecule resulting from a genetic defect in the fetus. Specifically, the CYP19A1 gene was found to have an insert of 87 bp, encoding 29 amino acids in-frame with no termination codon (107910.0003). By transient expression in COS-7 cells, the aromatase cDNA of the patient was found to contain a protein with a trace of activity. Harada et al. (1992) suggested that the defect in the placental aromatase gene, a feature of the infant's genotype, might be inherited since the parents were consanguineous in the 'fifth degree.' They showed that the offspring was homozygous for a defect that was present in heterozygous state in both parents (107910.0003).
In a brother and sister with aromatase deficiency, Morishima et al. (1995) identified homozygosity for a mutation in the aromatase gene (107910.0004).
Aromatase Excess Syndrome
In 3 patients with gynecomastia due to increased aromatase activity (139300), Shozu et al. (2003) identified 2 distinct heterozygous inversions in 15q21.2-q21.3 that resulted in a cryptic promoter in the aromatase gene, including part of the TMOD3 or CGNL1 promoter, respectively, and caused estrogen excess; see 107910.0010 and 107910.0011.
Breast Cancer Susceptibility
Siegelmann-Danieli and Buetow (1999) genotyped 348 Caucasian women with breast cancer (114480) and 145 Caucasian women controls for a published tetranucleotide repeat polymorphism in intron 4 of the CYP19 gene. Six common and 2 rare alleles were identified. The 171-bp allele was overrepresented in patients; of 14 individuals homozygous for this allele, 13 were patients. The control individual homozygous for this allele was a 46-year-old woman. The 171-bp allele was found to be associated with a silent polymorphism (G-to-A at val80). The relationship between the high-risk allele and cancer development remained to be elucidated.
Haiman et al. (2003) employed a haplotype-based approach to search for breast cancer-associated CYP19 variants in the Multiethnic Cohort Study (MEC). The authors observed significant haplotype effects, and also found a common long-range haplotype that was associated with increased risk of breast cancer. The authors hypothesized that women with the long-range CYP19 haplotype 2b-3c may be carriers of a predisposing breast cancer susceptibility allele.
Among 5,356 patients with invasive breast cancer and 7,129 controls composed primarily of white women of European descent, Haiman et al. (2007) found that common haplotypes spanning the coding and proximal 5-prime region of the CYP19A1 gene were significantly associated with a 10 to 20% increase in endogenous estrogen levels in postmenopausal women. The effect per copy of the A-A haplotype of SNPs rs749292 and rs727479 was the most significant (p = 4.4 x 10(-15)), although this accounted for less than 2% of the variation in estrogen levels. No significant associations with these SNPs or other common haplotypes were observed for breast cancer risk. Haiman et al. (2007) concluded that although genetic variation in CYP19A1 produced measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer.
Height
To determine whether CYP19 gene or Y chromosome loci are associated with variation in height, Ellis et al. (2001) performed an association study using common biallelic polymorphisms in CYP19 and the Y chromosome in 413 adult males and 335 females drawn at random from a large population sample. An association between CYP19 and height was found, but this was more evident in men than in women. An association was also found with the Y chromosome. Additionally, when men were grouped according to haplotypes of the CYP19 and Y chromosome polymorphisms, a difference of 4.2 cm was detected. The authors concluded that in men, genetic variation in CYP19 and on the Y chromosome are involved in determining normal adult height, and that these loci may interact in an additive fashion.
Bone Mineral Density
To assess the role of bioavailable estradiol and the CYP19 TTTA(n) repeat polymorphism in bone loss in elderly men, van Pottelbergh et al. (2003) performed a longitudinal study in a cohort of 214 healthy community-dwelling men aged 70 to 86. Bioavailable estrogen was consistently associated with prospectively assessed bone mineral density (BMD) changes at all measured sites. Moreover, the CYP19 TTTA(n) repeat polymorphism was an additional independent determinant of BMD changes at the distal forearm. Furthermore, the CYP19 genotype was associated with self-reported clinical fracture risk as well as fracture history in first-degree relatives. The authors concluded that the results of this study provided an indication that the aromatase enzyme may exert a direct modulatory action on bone metabolism at the tissue level in elderly men.
Gennari et al. (2004) studied the role of the TTTA repeat polymorphism in intron 4 of the CYP19 gene as a genetic determinant of BMD in a sample of elderly males who were recruited by direct mailing and followed longitudinally. Men with a high repeat genotype (more than 9 repeats) showed higher lumbar BMD values, lower bone turnover markers, higher estradiol levels, and a lower rate of BMD change than men with a low repeat genotype (fewer than 9 repeats). The association with BMD was not significant in the subgroup of patients with high body mass index (greater than 25), suggesting that the effect of CYP19 genotypes on bone may be masked by the increase in fat mass. Gennari et al. (2004) concluded that differences in estrogen levels due to polymorphism at the aromatase CYP19 gene may predispose men to increased age-related bone loss and fracture risk.
In a case-control study of 252 postmenopausal women aged 64.5 +/- 9.2 years (mean +/- SD), Somner et al. (2004) studied the association between 2 common polymorphisms in the CYP17 (609300) and CYP19 genes, -34T-C (Zmuda et al., 2001) and a silent G-to-A transition at val80 in exon 3 (Siegelmann-Danieli and Buetow, 1999), respectively, and bone mineral density (BMD) and serum androgen/estradiol. There was no significant difference in serum estradiol concentrations between osteoporosis cases and controls. The CYP19 genotype was significantly associated with serum estradiol (P = 0.002). Women with the AA genotype had higher serum estradiol concentrations compared with those with the GG genotype (P = 0.03). In older women, those with CYP19 GA and GG genotypes had an increased prevalence of osteoporosis (P = 0.04) and fractures (P = 0.003). Somner et al. (2004) found no significant association between CYP17 genotype and serum androgens and estradiol concentrations. However, a significant association was seen between BMD values at the femoral neck with CYP17 genotype in cases (P = 0.04) and in the whole study population (P = 0.012). Subjects with the CC genotype had significantly lower BMD (mean +/- SD: TT, 0.7 +/- 0.16; CC, 0.6 +/- 0.08 g/cm2; P = 0.006). Somner et al. (2004) concluded that both CYP17 and CYP19 are candidate genes for osteoporosis in postmenopausal women.
In a case-control study of 135 women with vertebral fractures due to postmenopausal osteoporosis and 312 controls, Riancho et al. (2007) studied 4 SNPs of the CYP19A1 gene (rs1062033, rs767199, rs4775936, and rs700518) and identified a common haplotype, present in about half the population, that was associated with an increased risk of fracture (OR, 1.8, p = 0.006). Total aromatase expression was 4 times lower in fat samples from homozygotes for the unfavorable alleles than in the opposite homozygotes (p = 0.007).
Leshin et al. (1981) showed that a similar lesion exists in the henny feathering trait of Sebright Bantam chickens. Further, they concluded that this trait results from a regulatory mutation affecting aromatase activity ( Leshin et al., 1981). George et al. (1990) showed that the henny feathering trait in the Golden Campine chicken is identical to that in the Sebright Bantam; indeed, it may be the same gene, the trait in the Campine having been derived from the Sebright. In the chicken the trait behaves as an incomplete dominant; heterozygotes express half the levels of extraglandular aromatase as do homozygotes on average.
Fisher et al. (1998) generated mice lacking functional aromatase enzyme by targeted disruption of the cyp19 gene. Male and female knockout mice were born with the expected mendelian frequency from F1 parents and grew to adulthood. At 9 weeks of age, female knockout mice displayed underdeveloped external genitalia and uteri. Ovaries contained numerous follicles with abundant granulosa cells and evidence of antrum formation that appeared arrested before ovulation. No corpora lutea were present. Additionally, the stroma were hyperplastic with structures that appeared to be atretic follicles. Development of the mammary glands approximated that of prepubertal females. Male mice of the same age showed essentially normal internal anatomy, but the male accessory sex glands were enlarged because of increased content of secreted material. The testes appeared normal. Male knockout mice were capable of breeding and produced litters of approximately average size. Whereas serum estradiol levels were at the limit of detection, testosterone levels were elevated, as were the levels of follicle-stimulating hormone and luteinizing hormone (see 152780). The phenotype of these animals differed markedly from that of the previously reported estrogen receptor knockout mice in which the estrogen receptor-alpha (ESR1; 133430) was deleted by targeted disruption.
Robertson et al. (1999) investigated spermatogenesis in mice that lack aromatase because of the targeted disruption of the cyp19 gene. Male mice deficient in aromatase were initially fertile but developed progressive infertility, until their ability to sire pups was severely impaired. The mice deficient in aromatase developed disruptions to spermatogenesis between 4.5 months and 1 year, despite no decreases in gonadotropins or androgens. Spermatogenesis primarily was arrested at early spermiogenic stages, as characterized by an increase in apoptosis and the appearance of multinucleated cells, and there was a significant reduction in round and elongated spermatids, but no changes in Sertoli cells or early germ cells. In addition, Leydig cell hyperplasia/hypertrophy was evident, presumably as a consequence of increased circulating luteinizing hormone. The findings indicated that local expression of aromatase is essential for spermatogenesis and provided evidence for a direct action of estrogen on male germ cell development and thus fertility.
Aromatase knockout (ArKO) mice, lacking a functional Cyp19 gene, cannot synthesize endogenous estrogens. Jones et al. (2000) examined the adipose deposits of male and female ArKO mice, observing that these animals progressively accumulated significantly more intraabdominal adipose tissue than their wildtype littermates, reflected in increased adipocyte volume at gonadal and infrarenal sites. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. A striking accumulation of lipid droplets was observed in the livers of ArKO animals. The findings demonstrated an important role for estrogen in the maintenance of lipid homeostasis in both males and females. Along the same lines, Heine et al. (2000) studied male and female Esr1 knockout mice and found that signaling by this receptor is critical in female and male white adipose tissue. Obesity in the males involved a mechanism of reduced energy expenditure rather than increased energy intake.
Yue et al. (2005) generated APP23 mice (see 104760), a mouse model of Alzheimer disease (AD; 104300), that were also estrogen-deficient due to heterozygous disruption of the aromatase gene. Compared to control APP23 mice with normal aromatase activity, the estrogen-deficient mice showed decreased brain estrogen, earlier onset of amyloid plaques, and increased brain beta-amyloid deposition. Microglia cultures from these mice showed impaired beta-amyloid clearance. In contrast, ovariectomized APP23 mice had normal brain estrogen levels and showed plaque pathology similar to control APP23 mice. In addition, Yue et al. (2005) found that postmortem brain tissue from 10 female AD patients showed 60% and 85% decreased levels of total and free estrogen, respectively, as well as decreased levels of aromatase mRNA compared to 10 female controls. However, serum estrogen levels were not different between the 2 groups. Yue et al. (2005) concluded that reduced brain estrogen production may be a risk factor for developing AD neuropathology.
Ito et al. (1993) described compound heterozygosity for 2 mutations in the CYP19 gene in a patient with aromatase deficiency (613546) suspected on the basis of clinical and biochemical evidence. The patient was an 18-year-old 46,XX female with sexual infantilism, primary amenorrhea, ambiguous external genitalia at birth, and polycystic ovaries. Coding exons 2 to 10 of the CYP19 gene were amplified by PCR from genomic DNA and sequenced directly. In exon 10, a C-to-T transition at bp 1303 resulted in a change of arginine-435 to cysteine (R435C). The results of RFLP analysis and direct sequencing of the amplified exon 10 DNA from the patient's mother indicated maternal inheritance of the R435C mutation. The other mutation, inherited from the father, was a G-to-A transition in exon 10 at bp 1310 resulting in a change of cysteine-437 to tyrosine (C437Y; 107910.0002). Transient expression experiments showed that the R435C mutant protein had approximately 1.1% of the activity of the wildtype, whereas C437Y was totally inactive.
For discussion of the cys437-to-tyr (C437Y) mutation in the CYP19A1 gene that was found in compound heterozygous state in a patient with aromatase deficiency (613546) by Ito et al. (1993), see 107910.0001.
Shozu et al. (1991) observed progressive virilization of a primigravida during pregnancy, as well as female pseudohermaphroditism of her baby, and showed that these conditions were caused by deficiency of placental aromatase activity (613546). Harada et al. (1992) showed that the aromatase gene from the placenta was transcribed as an abnormally large mRNA with an 87-bp insertion and was translated as an abnormally large protein molecule with 29 extra amino acids, resulting in an almost inactive enzyme. Harada et al. (1992) showed that the splice donor sequence (GT) of intron 6 in controls was mutated to GC in the patient, whereas the parents showed both GT and GC, indicating their heterozygous state.
Morishima et al. (1995) described a C-to-T transition at nucleotide 1123 in exon IX of the CYP19 gene in a 28-year-old XX proband and her 24-year-old XY sib. The mother of the proband exhibited signs of progressive virilization during both pregnancies that regressed postpartum. The XX proband, who was followed from infancy, exhibited the cardinal features of aromatase deficiency (613546). She had nonadrenal female pseudohermaphroditism at birth and underwent repair of the external genitalia, including a clitorectomy. At puberty, she developed progressive signs of virilization, pubertal failure with no signs of estrogen action, hypergonadotropic hypogonadism, polycystic ovaries on pelvic sonography, and tall stature. The basal concentrations of plasma testosterone, androstenedione, and 17-hydroxyprogesterone were elevated, whereas plasma estradiol was low. Hormone replacement therapy led to breast development, menses, resolution of ovarian cysts, and suppression of the elevated FSH and LH values. Her adult height was 177.6 cm. Her brother was 204 cm tall with eunuchoid skeletal proportions. He was sexually fully mature and had macroorchidism. The bone age was 14 years at a chronologic age of 24 years. Striking osteopenia was noted at the wrist and at other sites. The observations in these sibs were considered consistent with the following interpretations by Morishima et al. (1995): (1) estrogens are essential for normal skeletal maturation and proportions (but not linear growth) in men as well as in women, the accretion and maintenance of bone mineral density and mass, and the control of the rate of bone turnover; (2) estrogens have a significant role in the sex steroid-gonadotropin feedback mechanism in the male, even in the face of high circulating testosterone; (3) deficient estrogens in the adult male are associated with hyperinsulinemia and abnormal plasma lipids; and (4) placental aromatase has a critical role in protecting the female fetus from fetal masculinization and the pregnant woman from virilization.
Bilezikian et al. (1998) found that treatment for 3 years with conjugated estrogen resulted in restoration of bone mass in the patient reported by Morishima et al. (1995).
Mullis et al. (1997) reported a female with aromatase deficiency (613546) who was compound heterozygous for 2 point mutations in the CYP19 gene. The maternal allele had a basepair (C) deletion at codon 408 (CCC) that caused a frameshift resulting in a nonsense codon 111 bp (37 amino acids) 3-prime to the deletion. The paternal allele had a G-to-A transition at the 5-prime splice site (conserved GT to AT) between exon and intron 3 (IVS3+1G-A; 107910.0006). This mutation ignores the 5-prime splice site resulting in a read-through to a stop codon 3 bp downstream. Aromatase deficiency was suspected because of the marked prepartum virilization in the mother, and the diagnosis was confirmed shortly after birth. Extremely low levels of serum estrogens were found in contrast to high levels of androgens. Ultrasonographic studies of the child showed persistently enlarged ovaries containing numerous large cysts and normal-appearing large tertiary follicles at 2 years of age. Basal and GNRH-induced FSH levels remained strikingly elevated. Low-dose estradiol given for 50 days at the age of 3.5 years resulted in normalization of serum gonadotropin levels, regression of ovarian size, and increase of whole body and lumbar spine bone mineral density. The FSH levels and ovarian size returned to pretreatment levels 150 days after cessation of estradiol therapy.
For discussion of the splice site mutation in the CYP19A1 gene (IVS3+1G-A) that was found in compound heterozygous state in a patient with aromatase deficiency (613546) by Mullis et al. (1997), see 107910.0005.
In a man with aromatase deficiency (613546) whose parents were first cousins, Carani et al. (1997) identified a G-to-A transition at nucleotide 1094 in exon 9 of the P-450 aromatase gene, resulting in a glutamine instead of an arginine at codon 365. The mutation abolished a site cleaved by the restriction enzyme Acc651; restriction analysis showed that both parents were heterozygous for the mutation. Expression studies in COS-1 cells showed that the aromatase activity of the mutant protein was 0.4% of that of the wildtype protein in the presence of the same amount of total cellular protein. At 18 years of age the patient was 170 cm tall and he continued to grow, reaching a height of 187 cm at the age of 31 and 190 cm at the age of 38. Androgen therapy was ineffective; estrogen therapy resulted in increased spinal bone mineral density and complete epiphyseal closure after 9 months. The increases in bone mineral density, serum levels of alkaline phosphatase and osteocalcin, and urinary excretion of pyridinoline were similar to those that occurred during normal skeletal maturation during puberty. Thus, the authors proposed that eunuchoid skeletal features may result mainly from a deficiency of estrogen, rather than a deficiency of androgen. The lack of eunuchoid skeletal development in patients with complete androgen insensitivity supported this view. Skeletal pain, especially in the knees, was a clinical feature. At age 31 years his arm span was 204 cm and the ratio of upper segment to lower segment was 0.85. He showed bilateral genu valgum. There was no gynecomastia and penis size and pattern of pubic hair were normal. Psychosexual orientation was heterosexual and his libido and erections were normal.
Deladoey et al. (1999) identified a point mutation in the CYP19 gene that was responsible for aromatase deficiency (613546) in a 46,XY male infant with unremarkable clinical findings at birth. The boy was homozygous for a 1-bp deletion (codon 156, C) in exon 5 of the CYP19 gene. Aromatase deficiency was suspected prenatally because of the severe virilization of the mother during the early pregnancy, and the diagnosis was confirmed shortly after birth. Four weeks after birth, the boy showed extremely low levels of serum estrogens but had a normal level of serum free testosterone; in comparison with the high serum concentration of androstenedione at birth, a striking decrease occurred by 4 weeks postnatally. The authors had previously reported elevated basal and stimulated FSH levels in a female infant with aromatase deficiency in the first year of life. In contrast, in the male infant, basal FSH and peak FSH levels after standard GnRH stimulation tests were normal. The authors concluded that the contribution of estrogen to the hypothalamic-pituitary gonadotropin-gonadal feedback mechanism is different in boys and girls during infancy and early childhood. They hypothesized that in normal girls serum estradiol concentrations strongly correlate with circulating inhibin levels, and thus, low inhibin levels may contribute to the striking elevation of FSH in young girls with aromatase deficiency. In contrast, estradiol levels are physiologically about 7-fold lower in boys than in girls, and serum inhibin levels remain elevated even though levels of FSH, LH, and testosterone are decreased.
Herrmann et al. (2002) described a novel homozygous mutation in the CYP19 gene in a 27-year-old male with aromatase deficiency (613546) whose parents were consanguineous. A C-to-A substitution in intron 5 at position -3 of the splicing acceptor site before exon 6 of the CYP19 gene is the likely cause of loss of aromatase activity. The mRNA of the patient led to a frameshift and a premature stop codon 8 nucleotides downstream at the end of exon 5. Apart from genua valga, kyphoscoliosis, and pectus carinatum, the physical examination was normal, including secondary male characteristics with normal testicular size. To substitute for the deficiency, the patient was treated with 50 mg transdermal estradiol twice weekly for 3 months, followed by 25 mg twice weekly. Bone density of the distal radius increased and bone mineral density of the lumbar spine increased. Semen analysis revealed oligozoospermia. After 3 months of treatment, the sperm count increased and decreased rapidly during the following 3 months. The authors concluded that in this rare incidence of estrogen deficiency, estrogen replacement demonstrated its importance for bone mineralization and maturation and glucose metabolism in a male carrying a novel mutation in the CYP19 gene.
In a 36-year-old man and his 7-year-old son with severe gynecomastia of prepubertal onset and mild hypogonadotropic hypogonadism caused by elevated estrogen levels (139300), Shozu et al. (2003) identified an inversion on 15q21.2-q21.3 that moved the promoter of the FLJ14957 gene (CGNL1; 607856) into a 5-prime position in relation to the aromatase coding region. The father in this case had progressive gynecomastia and a linear growth spurt at the age of 5 years, which was quickly followed by the development of pubic hair and penile enlargement. He stopped growing at the age of 14 years when his height was below the first percentile. He underwent bilateral mastectomy at the age of 16 years. The son was born when the father was 30 years old. Physical examination demonstrated a high-pitched voice, lack of facial hair, mastectomy scars, and unremarkable external genitalia. In the son the gynecomastia and accelerated linear growth likewise first occurred at the age of 5 years: his height and weight were above the 99th percentile, breast development was Tanner stage III, and he had normal prepubertal external genitalia. At the chronologic age of 5.5 years, his bone age was 13 years.
Shozu et al. (2003) demonstrated that severe gynecomastia of prepubertal onset associated with elevated estrogen levels (139300) in a 17-year-old boy was caused by an inversion in 15q21.2-q21.3 that brought the promoter of the TMOD3 gene (605112) into a position immediately 5-prime of the aromatase gene.
In a 29-year-old man with aromatase deficiency (613546), Maffei et al. (2004) detected a homozygous G-to-A transition at the last nucleotide of exon 5 of the CYP19A1 gene that resulted in a glu210-to-lys (E210K) amino acid substitution. Continuing linear growth, eunuchoid body proportions, diffuse bone pain, and bilateral cryptorchidism were observed. The patient had a complex dysmetabolic syndrome characterized by insulin resistance, diabetes mellitus type 2, acanthosis nigricans, liver steatohepatitis, and signs of precocious atherogenesis. Testosterone treatment at high doses resulted in a severe imbalance in the estradiol-to-testosterone ratio together with insulin resistance and diabetes mellitus type 2. Estrogen treatment resulted in an improvement of acanthosis nigricans, insulin resistance, and liver steatohepatitis, coupled with a better glycemic control and the disappearance of 2 carotid plaques. Testis biopsy showed a pattern of total germ cell depletion that might be due to the concomitant presence of bilateral cryptorchidism. The authors concluded that this case of aromatase deficiency confirmed previous data on bone maturation and mineralization and revealed a high risk for the precocious development of cardiovascular disease in young aromatase-deficient men.
In a Russian kindred with aromatase excess syndrome (139300) with 16 affected individuals in 5 generations, Tiulpakov et al. (2005) detected heterozygosity for a novel chimeric transcript composed of exon 1 of the TRPM7 gene (605692) spliced to the common acceptor splice site of CYP19 exon 2. This rearrangement was predicted to result in aberrant aromatase expression driven by the TRPM7 promoter. In both sexes the disorder manifested in early childhood with breast enlargement, growth, and bone age acceleration. Tiulpakov et al. (2005) stated that the mechanism of this chromosomal defect appeared to be different from that described by Shozu et al. (2003) (see 107910.0010, 107910.0011), which most likely were the result of heterozygous inversions. The CYP19 and TRPM7 genes are transcribed in the same direction, with TRPM7 lying 3-prime (downstream) of CYP19. Thus, rearrangement bringing CYP19 under the control of the TRPM7 promoter could not result from simple inversion of the 15q21.2 portion. A more complex heterozygous rearrangement such as partial duplication of 15q21.2 with placing of the TRPM7 regulatory regions in front of the CYP19 coding exons would be required to produce the chimeric transcripts discovered in this study. Tiulpakov et al. (2005) were unable to determine the chromosomal breakpoints resulting in the chimeric CYP19 transcripts in this family.
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