Database: OMIMEntry: 107910
LinkDB: 107910
MIM Entry: 107910
Title:
+107910 CYTOCHROME P450, FAMILY 19, SUBFAMILY A, POLYPEPTIDE 1; CYP19A1
;;CYTOCHROME P450, SUBFAMILY XIX; CYP19;;
AROMATASE; ARO
AROMATASE DEFICIENCY, INCLUDED;;
PSEUDOHERMAPHRODITISM, FEMALE, DUE TO PLACENTAL AROMATASE DEFICIENCY,
INCLUDED;;
CYP19A1/CGNL1 FUSION GENE, INCLUDED;;
CYP19A1/TMOD3 FUSION GENE, INCLUDED;;
CYP19A1/TRPM7 FUSION GENE, INCLUDED
Text:
CLONING
Aromatase (EC 1.14.14.1), also called estrogen synthetase, is a
cytochrome P450 enzyme (CYP19) that catalyzes the formation of aromatic
C18 estrogens from C19 androgens. Using the amino acid sequence from the
N terminal of the molecule as described by Chen et al. (1986), Sparkes
et al. (1987) synthesized oligonucleotide probes and used them to screen
a human placental lambda gt11 cDNA expression library. Evans et al.
(1986) cloned and sequenced cDNA corresponding to this gene. Harada
(1988) isolated a complete cDNA clone encoding a human aromatase from a
human 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.
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. Corbin et al. (1988) cloned a
full-length cDNA for CYP19. The insert contained an open reading frame
encoding a protein of 503 amino acids. The sequence contains regions of
striking similarity to those of other members of the cytochrome P450
gene superfamily. The expressed protein is 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.
Using RT-PCR and semiquantitative RT-PCR, Sebastian et al. (2002) found
that CPY19 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 CPY19 was highly expressed in
breast cancer tissue and in breast adipose tissue adjacent to cancer.
GENE STRUCTURE
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.
MAPPING
Sparkes et al. (1987) used the cDNA they identified in cloning the CYP19
gene 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.
GENE FUNCTION
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.
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.
5-prime-RACE analysis 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.
Testicular expression of CYP19, the enzyme that converts androgens into
estrogens, has been shown in both somatic and germ cell types in several
species, whereas in humans, testicular expression is confined to the
somatic cells. Aquila et al. (2002) 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.
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.
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.
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.
BIOCHEMICAL FEATURES
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.
CLINICAL FEATURES
- Aromatase Deficiency
Aromatase, or estrogen synthetase, 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.
Aromatization of fetal adrenal androgens and their desulfation are
essential for production of estrogen in vivo by the human placenta. A
placental defect in desulfation, aromatization, or both results in low
urinary excretion of estrogens during pregnancy. Placental steroid
sulfatase deficiency is a well-documented disorder (308100). Mango et
al. (1978) reported the case of a primigravida who showed low urinary
estrogen excretion and demonstrated lack of placental aromatase activity
by in vitro assays. The first report of well-substantiated placental
aromatase deficiency appears to be that by Shozu et al. (1991). The
deficiency caused maternal virilization during pregnancy and
pseudohermaphroditism of the female fetus. Maternal serum levels of
estrogens were low and those of androgens were high in the third
trimester. The mother delivered vaginally a live, full-term, 46,XX
infant who showed male-appearing external genitalia with a greatly
enlarged phallus, complete fusion of posterior scrotolabial folds,
rugation of the scrotolabial folds, and a single meatus at the base of
the phallus. The maternal manifestations of virilization disappeared
gradually after delivery and the baby grew uneventfully. Levels of
immunologically reactive 17-beta-estradiol in the infant's serum were
normal at 2 to 6 months of age. It was unclear whether the aromatization
defect existed only in the placenta or in her entire body. If the defect
in aromatization is systemic, other enzymes besides aromatase may act on
aromatization.
Bulun (1996) reviewed aromatase deficiency including clinical features
in men and women, genotype/phenotype correlations, laboratory findings,
and a description of a possible animal model in spotted hyenas. As of
1996, 1 Japanese female infant (Shozu et al., 1991), 1 American
adolescent female (Conte et al., 1994), and 2 American adult sibs, 1
female and 1 male (Morishima et al., 1995), had been reported to have
P450arom gene defects. The phenotypes of these cases included maternal
virilization during the second half of pregnancy; clitoromegaly and
posterior labioscrotal fusion in newborn affected females; and absent
growth spurt, breast development, primary amenorrhea, virilization and
multicystic ovaries in adult affected females. While only 1 affected
male had been reported, normal genitalia were noted at birth, normal
pubertal development occurred, and adult stature was extremely tall
(greater than 3 SD) with osteoporosis, macroorchidism, and infertility
(Morishima et al. (1995); Bulun (1996)). The laboratory findings
included (1) extremely low maternal serum estradiol and estriol but very
high maternal serum testosterone in pregnant women; (2) high FSH and
undetectable estriol during infancy in affected females; (3) sonographic
findings of multicystic ovaries, high FSH and LH levels in affected
females during puberty; and (4) undetectable estradiol but very high FSH
and LH levels, unfused epiphyses and osteoporosis, and abnormal semen
analysis in the adult affected male (Bulun, 1996).
MOLECULAR GENETICS
Harada et al. (1992) demonstrated that aromatase is expressed only in
parts of the placenta and that the placental 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 CYP19 gene was found to have an insert of
87 bp, encoding 29 amino acids in-frame with no termination codon. The
insert was located at the splice point between exon 6 and intron 6 of
the normal gene, and the extra DNA fragment was the first part of intron
6 except that its initial GT was altered to GC. 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). Ito et al. (1993) described the molecular defects in the
CYP19 gene in what they claimed was the first example of fully
documented aromatase deficiency in an adult.
The brother and sister reported by Morishima et al. (1995) were shown to
have a mutation in the aromatase gene (107910.0004). The parents of
these sibs were of Italian descent and were consanguineous. Although
very tall with a eunuchoid appearance, the affected male was
heterosexual and sexually active. Macroorchidism, with an estimated
total testicular volume of 34 ml, was present. Bone age was 14.5 years;
only the proximal femoral epiphyses were fused. The ratio of upper
segment to lower segment was 0.84. Serum androgen concentrations were
all markedly elevated, but serum estrone and estradiol concentrations
were undetectable. Serum concentrations of FSH and LH were elevated.
Bone mass was reduced at all sites. After treatment with Premarin,
linear growth, which had been continuous, ceased and all epiphyses of
the hand and wrist were completely fused within 6 months. Serum LH and
FSH concentrations decreased to only slightly elevated levels. Estimated
testicular volume decreased from 34 to 28 ml. Bone mass increased
dramatically at all sites. There were no side effects of the estrogen
therapy. There was no change in libido or sexual orientation.
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 cases; of 14 individuals homozygous for this allele,
13 were cases. The control 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 which 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.
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.
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 nine
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 nine 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.
Binder et al. (2005) studied a family in which 7 affected males over 3
generations had inherited prepubertal gynecomastia in an autosomal
dominant manner. The maternal grandfather and 3 maternal uncles were
affected; all had been mastectomized. The mother of the proband had
normal age at menarche and no macromastia. Estrone levels of the proband
and the other affected boys were elevated, 17-beta-estradiol levels were
high normal, and testosterone levels were low. Hormonal analyses of the
affected adults, who had all fathered children, revealed pathologically
low serum testosterone levels but normal to high normal levels of
estradiol and estrone. A repeat polymorphism of the p450 aromatase gene
cosegregated with the disease phenotype in the family, making a mutation
of the p450 aromatase gene likely. SSCP analysis of alternative
untranslated exons and all coding exons of the p450 aromatase gene did
not indicate any mutation. In addition, FISH analysis using 4 probes
covering the promoter region did not reveal the presence of any major
inversion at this locus. The authors concluded that comparison of their
data with previous reports indicated that the hormonal, biochemical, and
genetic basis of the aromatase excess syndrome is heterogeneous.
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.
Lin et al. (2007) reported 4 patients (46,XX) from 3 kindreds with
variable degrees of androgenization and pubertal failure who were
homozygous or compound heterozygous for mutations in the CYP19A1 gene.
Functional studies revealed low residual aromatase activity in the
patients in whom breast development occurred, despite significant
androgenization in utero.
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 (dbSNP rs1062033, dbSNP rs767199,
dbSNP rs4775936, and dbSNP 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).
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 dbSNP rs749292
and dbSNP 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.
ANIMAL MODEL
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
animal 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
post-mortem 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.
Allelic Variants:
.0001
AROMATASE DEFICIENCY
CYP19A1, ARG435CYS
Ito et al. (1993) described compound heterozygosity for 2 mutations in
the CYP19 gene (see 107910.0002) in a case of aromatase deficiency
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. They indicated that this was the first definitive case of an
adult with aromatase deficiency to be reported. 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. 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. Transient
expression experiments showed that the R435C mutant protein had
approximately 1.1% of the activity of the wildtype, whereas C437Y was
totally inactive.
.0002
AROMATASE DEFICIENCY
CYP19A1, CYS437TYR
The patient reported by Ito et al. (1993), a compound heterozygote (see
107910.0001), additionally had a G-to-A transition in exon 10 at bp 1310
resulting in a change of cysteine-437 to tyrosine.
.0003
AROMATASE DEFICIENCY, PLACENTAL
CYP19A1, IVS6, T-C, +2
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. 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.
.0004
AROMATASE DEFICIENCY, PLACENTAL
CYP19A1, ARG375CYS
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, followed since infancy, exhibited the
cardinal features of the aromatase deficiency syndrome. 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.
This condition of estrogen deficiency, as well as the case of estrogen
resistance due to a mutation in the estrogen receptor (133430.0002)
reported by Smith et al. (1994), demonstrates that androgens are not
solely responsible for the establishment of peak bone mass in males; a
man with these 2 genetic disorders showed osteoporosis. 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).
.0005
AROMATASE DEFICIENCY
CYP19A1, 1-BP DEL, CODON 408, C
Mullis et al. (1997) reported a female who was a compound heterozygote
for 2 point mutations in the CYP19 gene. The maternal allele had a
basepair (C) deletion in codon 408 (CCC) that caused a frameshift
resulting in a nonsense codon 111 bp (37 amino acids) 3-prime to the
deletion. 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. See 107910.0006.
.0006
AROMATASE DEFICIENCY
CYP19A1, IVS3, G-A, +1
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). This
mutation ignores the 5-prime splice site resulting in a read-through to
a stop codon 3 bp downstream. See 107910.0005.
.0007
AROMATASE DEFICIENCY
CYP19A1, ARG365GLN
In a man 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 the time his height was 187 cm (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.
.0008
AROMATASE DEFICIENCY
CYP19A1, 1-BP DEL, CODON 156, C
Deladoey et al. (1999) identified a point mutation in the CYP19 gene
that was responsible for aromatase deficiency 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.
.0009
AROMATASE DEFICIENCY
CYP19A1, IVS4, C-A, -3
Herrmann et al. (2002) described a novel mutation of the CYP19 gene in a
27-year-old homozygous male of consanguineous parents. 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 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 oligoazoospermia. 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.
.0010
AROMATASE EXCESS SYNDROME
CYP19A1, INV, CGNL1 PROMOTER
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.
.0011
AROMATASE EXCESS SYNDROME
CYP19A1, INV, TMOD3 PROMOTER
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.
.0012
AROMATASE DEFICIENCY
CYP19A1, GLU210LYS
In a 29-year-old man with aromatase deficiency, 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 (125853), 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.
.0013
AROMATASE EXCESS SYNDROME
CYP19A1/TRPM7 FUSION
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.
See Also:
Berkovitz et al. (1985); George and Wilson (1980); Leibermann and
Zachmann (1992); Stratakis et al. (1998)
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Clinical Synopsis:
Thorax:
Gynecomastia
GU:
Normal male genitalia;
Early male sexual differentiation;
Normal hypothalamic-pituitary axis response
Growth:
Short final stature
Skel:
Advanced bone age
Misc:
Induced by follicle-stimulating hormone (FSH)
Lab:
Increased aromatase (estrogen synthetase) activity
Inheritance:
Autosomal dominant, male-limited (15q21.1);
AROMATASE DEFICIENCY
GU:
Female sexual infantilism;
Primary amenorrhea;
Ambiguous external genitalia at birth;
Polycystic ovaries
Lab:
Aromatase deficiency
Inheritance:
Autosomal recessive with compound heterozygosity
Contributors:
John A. Phillips, III - updated: 4/23/2009
Patricia A. Hartz - updated: 3/20/2009
Ada Hamosh - updated: 1/27/2009
Cassandra L. Kniffin - updated: 7/3/2008
John A. Phillips, III - updated: 2/13/2008
Marla J. F. O'Neill - updated: 12/17/2007
John A. Phillips, III - updated: 12/17/2007
John A. Phillips, III - updated: 5/18/2007
Paul J. Converse - updated: 11/9/2006
John A. Phillips, III - updated: 5/23/2006
John A. Phillips, III - updated: 4/25/2006
Cassandra L. Kniffin - updated: 3/31/2006
John A. Phillips, III - updated: 10/26/2005
George E. Tiller - updated: 9/12/2005
John A. Phillips, III - updated: 8/6/2004
Victor A. McKusick - updated: 6/3/2003
John A. Phillips, III - updated: 2/4/2003
John A. Phillips, III - updated: 1/29/2003
John A. Phillips, III - updated: 1/3/2003
John A. Phillips, III - updated: 10/31/2002
John A. Phillips, III - updated: 7/29/2002
John A. Phillips, III - updated: 7/26/2002
John A. Phillips, III - updated: 2/27/2002
Victor A. McKusick - updated: 9/14/2001
John A. Phillips, III - updated: 7/26/2001
Victor A. McKusick - updated: 11/30/2000
John A. Phillips, III - updated: 11/10/2000
Victor A. McKusick - updated: 8/10/1999
Ada Hamosh - updated: 5/18/1999
Victor A. McKusick - updated: 9/11/1998
Victor A. McKusick - updated: 6/30/1998
Victor A. McKusick - updated: 9/10/1997
John A. Phillips, III - updated: 6/28/1997
Victor A. McKusick - updated: 5/16/1997
John A. Phillips, III - updated: 1/18/1997
Creation Date:
Victor A. McKusick: 8/31/1987
Edit Dates:
terry: 12/16/2009
wwang: 5/4/2009
alopez: 4/23/2009
mgross: 3/23/2009
terry: 3/20/2009
alopez: 1/28/2009
terry: 1/27/2009
carol: 10/31/2008
wwang: 7/3/2008
ckniffin: 7/3/2008
carol: 2/13/2008
carol: 12/17/2007
alopez: 7/12/2007
alopez: 5/18/2007
mgross: 11/10/2006
terry: 11/9/2006
wwang: 10/6/2006
alopez: 5/23/2006
alopez: 4/25/2006
wwang: 4/5/2006
ckniffin: 3/31/2006
alopez: 10/26/2005
alopez: 10/4/2005
terry: 9/12/2005
alopez: 2/7/2005
alopez: 8/6/2004
carol: 7/1/2004
joanna: 3/17/2004
carol: 2/23/2004
carol: 8/8/2003
tkritzer: 7/17/2003
carol: 6/5/2003
terry: 6/5/2003
terry: 6/3/2003
carol: 3/5/2003
cwells: 2/4/2003
alopez: 1/29/2003
alopez: 1/3/2003
alopez: 10/31/2002
tkritzer: 7/29/2002
tkritzer: 7/26/2002
alopez: 2/27/2002
carol: 10/11/2001
carol: 9/19/2001
mcapotos: 9/18/2001
mcapotos: 9/14/2001
mgross: 7/26/2001
mgross: 12/4/2000
terry: 11/30/2000
terry: 11/10/2000
alopez: 8/23/1999
terry: 8/10/1999
alopez: 5/24/1999
terry: 5/18/1999
carol: 10/12/1998
carol: 9/16/1998
terry: 9/11/1998
alopez: 7/6/1998
terry: 6/30/1998
terry: 5/29/1998
terry: 9/16/1997
terry: 9/10/1997
jenny: 9/2/1997
jenny: 5/28/1997
alopez: 5/27/1997
alopez: 5/20/1997
terry: 5/16/1997
mark: 3/27/1997
mark: 3/6/1997
mark: 2/2/1996
terry: 1/25/1996
mimadm: 4/18/1994
carol: 3/28/1994
carol: 12/22/1992
carol: 12/14/1992
carol: 6/11/1992
carol: 5/5/1992
OMIM
DBGET integrated database retrieval system
