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Alternative titles; symbols
1,25-@DIHYDROXYVITAMIN D3 RECEPTOR VITAMIN D HORMONE
RECEPTOR
Gene map locus 12q12-q14
TEXT
DESCRIPTION
The vitamin D3 receptor (VDR) is an intracellular hormone
receptor that specifically binds the active form of vitamin D
(1,25-dihydroxyvitamin D3 or calcitriol) and interacts with
target-cell nuclei to produce a variety of biologic effects (Baker
et al., 1988).
CLONING
Baker et al. (1988) isolated a cDNA corresponding to the human
vitamin D receptor from a human intestinal cDNA library. The
deduced 427-amino acid protein has a calculated molecular mass of
48.3 kD and belongs to the superfamily of trans-acting
transcriptional regulatory factors, including the steroid and
thyroid hormone receptors. The VDR protein contains a zinc-finger
DNA-binding and transcriptional activation domain and a
ligand-binding domain. VDR is closely related to the thyroid
hormone receptors. RNA blot hybridization indicated a single RNA
species of about 4.6 kb.
GENE STRUCTURE
Miyamoto et al. (1997) determined that the VDR gene contains 11
exons and spans approximately 75 kb. The noncoding 5-prime end of
the VDR gene includes exons 1A, 1B, and 1C, while its translated
product is encoded by 8 additional exons (2-9). Three unique mRNA
isoforms are produced as a result of the differential splicing of
exons 1B and 1C. The DNA sequence upstream to exon 1A is GC-rich
and does not contain an apparent TATA box. Several potential
binding sites for the transcription factor SP1 (189906) and other
activators were noted. An intron fragment 3-prime of exon 1C
conferred retinoic acid responsivity when fused to a reporter gene
plasmid.
Exons 2 and 3 of the VDR gene are involved in DNA binding, and
exons 7, 8, and 9 are
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*601769 GeneTests, LinksVITAMIN D RECEPTOR; VDR
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involved in binding to vitamin D (Hughes et al., 1988).
GENE FUNCTION
Using mutation analysis, Jurutka et al. (2000) characterized
arg18/arg22, VDR residues immediately N-terminal of the first
DNA-binding zinc finger, as vital for contact with the general
transcription factor IIB (TFIIB; 189963). A natural polymorphic
variant of VDR, termed F/M4 (missing a FokI restriction site),
which lacks only the first 3 amino acids (including glu2),
interacted more efficiently with TFIIB and also possessed elevated
transcriptional activity compared with the full-length (f/M1)
receptor. The authors concluded that the functioning of positively
charged arg18/arg22 as part of a VDR docking site for TFIIB is
influenced by the composition of the adjacent polymorphic N
terminus. Increased transactivation by the F/M4 neomorphic VDR was
hypothesized to result from its demonstrated enhanced association
with TFIIB.
Makishima et al. (2002) demonstrated that the vitamin D receptor
also functions as a receptor for the secondary bile acid
lithocholic acid, which is hepatotoxic and a potential enteric
carcinogen. The vitamin D receptor is an order of magnitude more
sensitive to lithocholic acid and its metabolites than are other
nuclear receptors. Activation of the vitamin D receptor by
lithocholic acid or vitamin D induced expression in vivo of CYP3A
(124010), a cytochrome P450 enzyme that detoxifies lithocholic acid
in the liver and intestine. Makishima et al. (2002) suggested a
mechanism that may explain the proposed protective effect of
vitamin D and its receptor against colon cancer.
Kitagawa et al. (2003) identified a human multiprotein complex
that directly interacts with VDR through the WSTF gene (BAZ1B;
605681). They designated the complex WINAC (WSTF-including
nucleosome assembly complex) and determined that it contains at
least 13 components. WINAC has ATP-dependent chromatin-remodeling
activity and contains both SWI/SNF components and DNA
replication-related factors. WINAC mediates the recruitment of
unliganded VDR to its target sites in promoters, while subsequent
binding of coregulators requires ligand binding. This recruitment
order exemplifies that an interaction of a sequence-specific
regulator with a chromatin-remodeling complex can organize
nucleosomal arrays at specific local sites in order to make
promoters accessible for coregulators. Overexpression of WSTF
restored the impaired recruitment of VDR to vitamin D-regulated
promoters in fibroblasts from patients with Williams syndrome
(194050). This finding suggested that WINAC dysfunction may
contribute to the phenotypic variability of Williams syndrome.
Using retroviral transduction, Palmer et al. (2004) generated
human SW480-ADH colon cancer cells that ectopically express mouse
hemagglutinin-tagged Snai1 (604238) protein (SNAIL-HA).
Overexpression of Snai1 in these cells resulted in lower vitamin D
receptor mRNA and protein expression and inhibited induction of
E-cadherin (192090) and VDR by 1,25(OH)2D3. A 1,25(OH)2D3 analog
inhibited tumor growth in immunodeficient mice injected with mock
cells, but not in those injected with SNAIL-HA cells. In 32 paired
samples of normal colon and tumor tissue from patients undergoing
colorectal surgery, Palmer et al. (2004) found that high SNAI1
expression in tumor tissue correlated with downregulation of VDR
and E-cadherin (p = 0.007 and 0.0073, respectively). Palmer et al.
(2004) concluded that the balance between VDR and SNAI1 expression
is critical for E-cadherin expression, which influences cell fate
during colon cancer progression.
Healy et al. (2005) administered human PTH (168450) over 48
hours to wildtype mice and observed a 15% reduction in renal VDR
levels (p less than 0.03). When the authors similarly administered
PTH to CYP27B1 (609506)-null mice, which are incapable of
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endogenously producing vitamin D hormone, they observed a 29%
reduction in VDR levels (p less than 0.001). Healy et al. (2005)
concluded that PTH is a potent downregulator of VDR expression in
vivo.
Shah et al. (2006) stated that the signaling and oncogenic
activity of beta-catenin (CTNNB1; 116806) can be repressed by
activation of VDR. Conversely, high levels of beta-catenin can
potentiate the transcriptional activity of 1,25-dihydroxyvitamin
D3. Shah et al. (2006) showed that the effects of beta-catenin on
VDR activity are due interaction between the activator function-2
domain of VDR and the C terminus of beta-catenin.
Using DNA microarray and quantitative PCR analyses, Liu et al.
(2006) found that activation of TLR2 (603028) and TLR1 (601194) by
a mycobacterial ligand upregulated expression of VDR and CYP27B1,
the vitamin D 1-hydroxylase that catalyzes the conversion of
vitamin D to its active form, in monocytes and macrophages, but not
dendritic cells. Intracellular flow cytometric and quantitative PCR
analyses showed that treatment of monocytes with vitamin D
upregulated expression of CYP24 (CYP24A1; 126065), the vitamin D
24-hydroxylase, and cathelicidin (CAMP; 600474), an antimicrobial
peptide, but not DEFB4 (602215). Confocal microscopy demonstrated
colocalization of CAMP with bacteria-containing vacuoles of vitamin
D-treated monocytes, and vitamin D treatment of M.
tuberculosis-infected macrophages reduced the number of viable
bacilli. Ligand stimulation of TLR2 and TLR1 upregulated CYP24 and
CAMP in the presence of human serum, but not bovine serum, and CAMP
upregulation was more efficient in Caucasian than in African
American serum, in which vitamin D levels were significantly lower.
Vitamin D supplementation of African American serum reversed the
CAMP induction defect. Liu et al. (2006) proposed that vitamin D
supplementation in African and Asian populations, which may have a
reduced ability to synthesize vitamin D from ultraviolet light in
sunlight, might be an effective and inexpensive intervention to
enhance innate immunity against microbial infection and neoplastic
disease.
MAPPING
Faraco et al. (1989), who identified an ApaI dimorphism at the
VDR locus, assigned the VDR gene to chromosome 12 by somatic cell
hybrid studies. By study of rat/human somatic cell hybrids, Szpirer
et al. (1991) showed that the VDR gene is located on 12q in the
human and chromosome 7 in the rat. Labuda et al. (1991) assigned
the VDR gene to 12q12-q14 by in situ hybridization. No
recombination was found between VDR and COL2A1 (120140; lod = 1.94)
or ELA1 (130120; lod = 0.98) on 12q13. The COL2A1 and VDR loci are
separated by less than 740 kb, with VDR distal to COL2A1 (Pedeutour
et al., 1994).
MOLECULAR GENETICS
Vitamin D-Dependent Rickets Type II
In 2 patients with vitamin D-dependent rickets type II (VDDR II;
277440), Hughes et al. (1988) identified 2 different mutations in
the VDR gene (601769.0001 and 601769.0002). Hughes et al. (1988)
suggested that this was the first molecular identification of a
disease-producing mutation in a steroid hormone receptor gene.
(Mutations were found at about the same time in the androgen
receptor; see 313700.)
Saijo et al. (1991) noted that different mutations in the VDR
gene have been specific for particular ethnic groups: Arabian
(601769.0002 and 601769.0003), Haitian (601769.0001), North African
(601769.0004), and Japanese (601769.0005).
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Miller et al. (2001) reported a patient with type II vitamin
D-resistant rickets who was compound heterozygous for 2 mutations
in the VDR gene (601769.0013, 601769.0014). Similar to patients
with mutations in HR (602302), follicular remnants in this
patient's skin appeared to possess hair follicle stem cells, some
of which generated cutaneous cysts. These and other findings
suggested that VDR and HR, which are both zinc finger proteins, may
be in the same genetic pathway that controls postnatal cycling of
the hair follicle.
Role in Bone Mineral Density (BMD) and Osteoporosis
Studies on the role of polymorphisms in the VDR gene in the
determination of bone mineral density have been conflicting. Most
of the studies (see below) identified the restriction fragment
length polymorphisms (RFLPs) Bb, Tt, Aa, and Ff, as defined by the
endonucleases BsmI, TaqI, and ApaI, FokI, respectively. The
lowercase allele contains the restriction site, whereas the
uppercase allele does not.
Calcitriol, the active hormonal form of vitamin D, acts through
the vitamin D receptor and a specific vitamin D-responsive element
to induce the synthesis of osteocalcin (BGLAP; 112260), the most
abundant noncollagenous protein in bone. In studies of twins,
variation in serum osteocalcin levels was shown to have a major
genetic component (Kelly et al., 1991) and to be closely correlated
with the genetic diversity in bone density (Pocock et al., 1987).
Morrison et al. (1992) presented evidence suggesting that VDR
polymorphisms may influence serum levels of osteocalcin.
Among 311 healthy women from Sydney, 207 of whom were
postmenopausal, Morrison et al. (1994) found an association between
the BB VDR genotype and lower bone mineral density. However,
Hustmyer et al. (1994) found no relationship between several VDR
polymorphisms and bone mineral density at spine, femur, and forearm
among 86 monozygotic and 39 dizygotic adult female twin pairs. In
Korea, Lim et al. (1995) found that no patients with osteoporosis
had the BB genotype. In a study in the northeast of Scotland,
Houston et al. (1996) found that individuals with the BB genotype
had a higher femoral neck bone density than individuals with the bb
genotype, the opposite of the finding in the study of Morrison et
al. (1994). Among 44 patients with severe osteoporosis with
vertebral compression fractures, Houston et al. (1996) found no
association with the VDR genotype.
Garnero et al. (1996) found no relationship between VDR genotype
and bone mass, bone turnover, or bone loss among 268 untreated
postmenopausal women. Ensrud et al. (1999) found no association
between VDR genotype and fracture risk among 9,704 women aged 65
years or older.
Among a group of prepubertal American girls of Mexican descent,
Sainz et al. (1997) found that girls with the aa and bb genotypes
had 2 to 3% higher femoral bone density and an 8 to 10% higher
vertebral bone density than girls with AA and BB genotypes.
However, there was no association between the cross-sectional area
of the vertebrae or the cross-sectional or cortical area of the
femur and the vitamin D receptor genotype. Riggs (1997) quoted a
remark by Charles Dent of University College, London, that 'senile
osteoporosis is a pediatric disease.'
Among healthy prepubertal white Australian children aged 7
years, Tao et al. (1998) found that females homozygous for the t
Taq1 allele had lower BMD than TT homozygotes in certain bone
regions; tt homozygotes were also significantly shorter and
lighter. These effects were not observed in males. The authors
suggested that the VDR may play a more important role in trabecular
bone than in cortical bone, and that VDR allelic variation
might
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be responsible for some of the variation in BMD and postnatal
growth in prepubertal girls.
In a group of men, Ferrari et al. (1999) found that BB
homozygotes had significantly lower BMD only in subjects also
carrying the f allele at the VDR 5-prime polymorphic site (FokI).
Serum PTH levels were significantly higher in the BB genotype at
baseline and remained so under either a low or a high
calcium-phosphorus diet. Moreover, on the low calcium-phosphorus
diet, BB subjects had significantly decreased tubular Pi
reabsorptive capacity and plasma Pi levels. The authors emphasized
the importance of identifying multiple single-base mutation
polymorphisms, and suggested a role for environmental/dietary
factor interactions with VDR gene polymorphisms in peak bone
mineral mass in men.
Uitterlinden et al. (2001) found that a haplotype represented by
polymorphisms in the VDR gene and the presence of the COL1A1 gene
Sp1-binding site polymorphism 2046G-T (120150.0051) exhibited a
combined influence on osteoporotic fracture risk, independent of
BMD.
Among 426 Italian postmenopausal women, Gennari et al. (1998)
found an association between certain VDR polymorphisms and lumbar
spine BMD as well as the development of osteoporosis. Colin et al.
(2003) studied the combined influence of polymorphisms in both the
estrogen receptor gene (ESR1; 133430) and the VDR gene on the
susceptibility to osteoporotic vertebral fractures in 634 women
aged 55 years and older. Three VDR haplotypes (1, 2, and 3) of the
BsmI, ApaI, and TaqI RFLPs and 3 ESR1 haplotypes (1, 2, and 3) of
the PvuII and XbaI RFLPs were identified. ESR1 haplotype-1 was
dose-dependently associated with increased vertebral fracture risk
corresponding to an odds ratio of 1.9 (95% CI, 0.9-4.1) per copy of
the risk allele. VDR haplotype-1 was also overrepresented in
vertebral fracture cases. These associations were independent of
BMD.
Nejentsev et al. (2004) studied population differences in
single-nucleotide polymorphisms (SNPs) of the VDR gene. Fang et al.
(2005) determined sequence variation across the major relevant
parts of VDR, including construction of linkage disequilibrium
blocks and identification of haplotype alleles. They analyzed 15
haplotype-tagging SNPs in relation to 937 clinical fractures
recorded in 6,148 elderly whites over a follow-up period of 7.4
years. Haplotype alleles of the promoter region and of the 3-prime
untranslated region (UTR) was strongly associated with increased
fracture risk. For the 16% of subjects who had risk genotypes at
both regions, their risk increased 48% for clinical fractures (P =
0.0002), independent of age, sex, height, weight, and bone mineral
density. The population-attributable risk varied between 1% and 12%
for each block and was 4% for the combined VDR risk genotypes. Fang
et al. (2005) showed further a 30% increased mRNA decay in an
osteoblast cell line for a construct carrying the 3-prime-UTR risk
haplotype (P = 0.02). This comprehensive candidate gene analysis
demonstrated that the risk allele of multiple VDR polymorphisms
results in lower VDR mRNA levels. This could impact the vitamin D
signaling efficiency and might contribute to the increased fracture
risk observed for these risk haplotype alleles.
In a multicenter large-scale association study of over 26,000
individuals enrolled from 9 European teams, Uitterlinden et al.
(2006) found no association between bone mineral densities at the
lumbar spine and femoral neck or fracture risk and the FokI, BsmI,
ApaI, or TaqI VDR polymorphisms. There was a modest risk reduction
(9%) for vertebral fractures associated with the Cdx2 promoter A
allele (rs11568820).
Garnero et al. (2005) investigated the relationships between VDR
genotypes and fracture
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risk. A total of 589 postmenopausal women (mean age, 62 years)
were followed prospectively during a median (interquartile) of 11
(1.1) years. VDR allele B was significantly and dose dependently
overrepresented in women who fractured, including 34 and 86 women
with first incident vertebral and nonvertebral fragility fractures,
respectively. This corresponded to an odds ratio of 1.5 (95%
confidence interval, 0.95-2.40) for heterozygous carriers (bB, n =
286) and 2.10 (95% confidence interval, 1.16-3.79) for homozygous
carriers (BB, n = 90) of the B allele, compared with women with the
bb genotype (n = 213). The authors concluded that VDR genotypes are
associated with the risk of fracture in postmenopausal women
independently of BMD, rate of postmenopausal forearm BMD loss, bone
turnover, and endogenous hormones.
Role in Height and Overall Growth
Among 589 healthy 2-year-old infants, Suarez et al. (1997) found
that homozygous BB girls had higher length, weight, and body
surface area, and inversely, BB boys had lower weight, body mass
index, and body surface area, than their respective bb
counterparts. As a result, gender-related differences were observed
in Bb and bb, but not in BB populations. These associations with
VDR genotype were also observed at birth and at 10 months of age in
the longitudinal analysis of 145 selected full-term babies
homozygous for the BsmI polymorphism. The authors concluded that
the VDR genotype may influence intrauterine and early postnatal
growth.
Among 90 healthy Caucasian males, Lorentzon et al. (2000) found
that boys with the BB VDR genotype were shorter at birth and grew
less from birth until after puberty than their Bb and bb
counterparts. The BB boys had lower bone area of the humerus,
femur, and total body (p less than 0.05) than the Bb and bb boys;
however, the VDR polymorphisms were not related to BMD at any site.
The authors concluded that a prediction model including parental
height, birth height, birth weight, and VDR alleles could predict
up to 39% of the total variation in adult height in their study
population. The VDR allelic variants alone contributed to 8% of the
total variation. See STQTL3 (606257).
In a study of 1,873 white subjects from 406 nuclear families,
Xiong et al. (2005) found within-family associations with height at
BsmI and TaqI loci (p = 0.048 and 0.039, respectively). Analyses
based on BsmI/TaqI haplotypes showed linkage (p = 0.05) and
association (p = 0.001) with height. The bT haplotype had the most
significant and consistent total and within-family associations (p
= 0.0006 and 0.033, respectively), and subjects with the bT
haplotype were an average of 1% (1.6 cm) taller than those without
it (p = 0.003). The authors noted that this association might be
female-specific and influenced by menstrual status. Xiong et al.
(2005) suggested that VDR may be linked to and associated with
adult height variation in white populations.
Role in Hyperparathyroidism
Among 206 Caucasian patients with sporadic primary
hyperparathyroidism (see 145000), Carling et al. (1997) found that
the VDR b, a, and T alleles were overrepresented in 100 menopausal
females with sporadic hyperparathyroidism equivalent.
Hyperparathyroidism appeared to be unrelated to the VDR
polymorphisms in patients with hyperparathyroidism of multiple
endocrine neoplasia type I (MEN1; 131100) and patients with
hyperparathyroidism of uremia. By in vitro studies of parathyroid
adenomas, Carling et al. (1997) found an association between
calcium-mediated PTH secretion and inhibition suppression and VDR
genotype. Carling et al. (1998) found that parathyroid tumors from
patients homozygous for the VDR b, a, or T alleles showed
significantly lower VDR and higher PTH mRNA levels than those from
patients with BB, AA, or tt genotypes (p less than
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0.0001-0.02), whereas those from heterozygotes had intermediate
values. A similar discrepancy was found when comparing the baT and
non-baT haplotypes (0.042 +/- 0.005 vs 0.064 +/- 0.004 for VDR;
34.4 +/- 3.7 vs 21.6 +/- 2.2 for PTH; both p less than 0.005). The
authors concluded that the lower VDR mRNA levels associated with
the b, a, and T alleles may affect the calcitriol-mediated control
of parathyroid function and thereby contribute to the development
of sporadic primary hyperparathyroidism.
Correa et al. (1999) found no association between the VDR FokI
polymorphism and the development of sporadic primary
hyperparathyroidism among 182 postmenopausal women compared to
controls. There were no significant associations with age, serum
calcium, serum PTH, BMD, or parathyroid tumor weight. The authors
concluded that the FokI polymorphism has at most a minor pathogenic
importance in the development of the disorder.
Other Disease Associations
Uitterlinden et al. (1997) found overrepresentation of 1 VDR
haplotype and radiographic osteoarthritis and osteophytes at the
knee. Adjustment for bone density at the femoral neck did not
change these results, indicating that the association was not
mediated by bone density. The authors raised the possibility of
linkage disequilibrium with the closely situated COL2A1 gene, which
encodes cartilage collagen.
Among 104 Korean patients with psoriasis (177900), Park et al.
(1999) found a significant increase in the frequency of the VDR A
polymorphism compared to controls. This tendency was more marked in
early-onset psoriasis. Derived allele frequencies on the basis of
Hardy-Weinberg equilibrium for A and a were 0.317 and 0.683 in the
psoriasis group and 0.168 and 0.832 in the control group,
respectively, while in the early-onset group, A increased to
0.354.
Ban et al. (2000) presented evidence suggesting an association
between the VDR B polymorphism and Japanese patients with Graves
disease (275000).
Motohashi et al. (2003) found a significantly higher frequency
of the VDR B allele among 203 patients with acute onset of type I
diabetes (222100) compared with 222 controls (p = 0.0010).
Selvaraj et al. (2004) presented evidence suggesting that
polymorphisms in the VDR gene may predispose to spinal tuberculosis
(see 607948).
ANIMAL MODEL
Yoshizawa et al. (1997) found that VDR-null mice displayed no
defect in development and growth before weaning, irrespective of
reduced expression of vitamin D target genes. After weaning,
however, mutants failed to thrive, with appearance of alopecia,
hypocalcemia, and infertility, and bone formation was severely
impaired as a typical feature of vitamin D-dependent rickets type
II. Unlike humans with this disease, most of the VDR-null mice died
within 15 weeks after birth, and uterine hypoplasia with impaired
folliculogenesis was found in female reproductive organs. These
defects, such as alopecia and uterine hypoplasia, were not observed
in vitamin D-deficient animals. Uterine hypoplasia was shown to be
due to lack of estrogen synthesis in the mutant ovaries; the uterus
in these animals responded normally to administration of estrogen.
Male reproductive organs appeared normal in VDR-null mice. Uterine
hypoplasia, infertility, and early lethality are not pronounced in
patients with vitamin D-dependent rickets type II, possibly because
of therapy with calcium
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supplements. The higher content of calcium in murine milk than
in human milk may keep serum calcium levels normal, thereby
ensuring normal growth of VDR-null mice before weaning. The
findings of Yoshizawa et al. (1997) established a critical role for
VDR in growth, bone formation, and female reproduction in the
postweaning stage.
The active metabolite of vitamin D, 1,25(OH)2D3, modulates the
immune response in Th1-related diseases. Using an experimental
allergic asthma model, Wittke et al. (2004) found that, apart from
upregulation of 2 Th2-related genes, 1,25(OH)2D3 had no affect on
asthma severity in wildtype mice. Asthma-induced Vdr-deficient
mice, however, failed to develop airway inflammation, airway
hyperresponsiveness, or eosinophilia, despite high IgE
concentrations and elevated Th2 cytokines. Wittke et al. (2004)
suggested that the vitamin D endocrine system has an important role
in the development of Th2-driven inflammation in the lung.
During development and postnatal growth of the endochondral
skeleton, proliferative chondrocytes differentiate into
hypertrophic chondrocytes, which subsequently undergo apoptosis and
are replaced by bone. Donohue and Demay (2002) found that Vdr-null
mice who developed rickets had expansion of hypertrophic
chondrocytes due to impaired apoptosis of these cells. Sabbagh et
al. (2005) showed that institution of a rescue diet that restored
mineral ion homeostasis in Vdr-null mice prevented the development
of rachitic changes, indicating that mineral ion abnormalities, not
ablation of the Vdr gene, were the cause of impaired chondrocyte
apoptosis. Similarly, 'Hyp' mice with rickets due to mutation in
the Phex gene (300550) also showed impaired apoptosis of
hypertrophic chondrocytes, and the decreased apoptosis was
correlated with hypophosphatemia. Wildtype mice rendered
hypercalcemic and hypophosphatemic by dietary means also developed
rickets. In vitro studies showed that the apoptosis was mediated by
caspase-9 (CASP9; 602234). Sabbagh et al. (2005) concluded that
hypophosphatemia was the common mediator of rickets in these mice.
The findings indicated that normal phosphorus levels are required
for growth plate maturation and that circulating phosphate is a key
regulator of hypertrophic chondrocyte apoptosis.
Masuyama et al. (2006) generated mice with conditional
inactivation of Vdr in chondrocytes. Growth-plate chondrocyte
development was not affected by lack of Vdr, but vascular invasion
was impaired, and osteoclast number was reduced in juvenile mice,
resulting in increased trabecular bone mass. Vdr signaling in
chondrocytes directly regulated osteoclastogenesis by inducing
Rankl (TNFSF11; 602642) expression. Mineral homeostasis was also
affected in mutant mice. In vivo and in vitro analysis indicated
that Vdr inactivation in chondrocytes reduced expression of Fgf23
(605380) by osteoblasts and consequently led to increased renal
expression of 1-alpha-hydroxylase (CYP27B1) and sodium/phosphate
cotransporter type IIA (SLC34A1; 182309). Masuyama et al. (2006)
concluded that VDR signaling in chondrocytes is required for timely
osteoclast formation during bone development and for endocrine
action of bone in phosphate homeostasis.
Froicu et al. (2006) compared mice lacking Il10 (124092), which
develop inflammatory bowel disease (IBD; see 266600), with
double-knockout (DKO) mice lacking Il10 and Vdr. They observed
normal thymic development and peripheral T-cell numbers in DKO mice
up to 3 weeks of age. However, following onset of IBD, the thymus
became dysplastic with reduced cellularity and increased apoptosis.
Spleen weight increased due to red blood cell accumulation, but
there was a 50% reduction in lymphocytes. In contrast, mesenteric
lymph nodes of DKO mice were enlarged and had increased lymphocyte
numbers. DKO T cells were hyporesponsive. RT-PCR detected
overexpression of inflammatory cytokines (e.g., IL1B; 147720) in
DKO colon. Froicu et al. (2006) concluded that Vdr expression is
required for T-cell control of inflammation in Il10-deficient
mice.
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ALLELIC VARIANTS (selected examples)
.0001 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, GLY33ASP]
In 2 affected sisters from a black Haitian family with vitamin
D-dependent rickets type II (277440), Hughes et al. (1988)
identified a G-to-A transition in exon 2 of the VDR gene, resulting
in a gly30-to-asp (GLY30ASP) substitution near the tip of the first
zinc finger. Based on corrected sequencing, the mutation is gly33
to asp.
.0002 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, ARG73GLN]
In 2 affected brothers from an Arab family living in the Middle
East with vitamin D-dependent rickets type II (277440), Hughes et
al. (1988) identified a mutation in the VDR gene, resulting in an
arg70-to-gly (ARG70GLY) substitution at the tip of the second zinc
finger of the vitamin D receptor. Based on corrected sequencing,
the mutation is arg73 to gln.
.0003 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, TYR292TER]
In 4 affected children from 3 related Middle Eastern Arabic
families with a classic form of vitamin D-dependent rickets type II
(277440) and absence of detectable binding of vitamin D to the
vitamin D receptor in cultured fibroblasts or lymphoblasts, Ritchie
et al. (1989) identified a 970C-A transversion in exon 7 of the VDR
gene, resulting in a tyr292-to-ter (Y292X) substitution. The Y292X
mutation caused a truncation of the VDR protein, thereby deleting a
large portion of the steroid hormone-binding domain (amino acids
292-424). The 4 parents tested showed both wildtype and mutant
alleles. Also see Malloy et al. (1990).
.0004 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, ARG77GLN]
In 2 unrelated patients with vitamin D-dependent rickets type II
(277440), Sone et al. (1990)identified a homozygous 327G-A
transition in exon 3 of the VDR gene, resulting in an arg77-to-gln
(R77Q) substitution at a highly conserved residue. In vitro
functional expression studies showed that the R77Q mutant receptor
bound 1,25-dihydroxyvitamin D3 with normal affinity, but displayed
weak affinity for the nuclear fraction and for heterologous DNA.
Significantly, the protein was inactive in promoting transcription
in a cotransfection assay using a chloramphenicol acetyltransferase
gene reporter fused downstream of the VDR-inducible osteocalcin
gene promoter-enhancer. The patients were of North African
ancestry.
.0005 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, ARG47GLN]
Takeda et al. (1989) described 2 sibs, children of first-cousin
parents, with vitamin D-dependent rickets with alopecia (277440).
In these 2 sibs and in another patient with VDDR type II, Saijo et
al. (1991) identified a 140G-A transition in exon 3 of the VDR
gene, resulting in an arg47-to-gln (R47Q) substitution between 2
zinc fingers. The affected residue is conserved in all steroid
hormone receptors. Single-strand conformation polymorphism analysis
of amplified DNA confirmed that all 3 patients were homozygous and
that parents from 1 family were heterozygous carriers.
.0006 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, GLN149TER]
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In a child of Middle Eastern origin with vitamin D-dependent
rickets type II (277440), Kristjansson et al. (1993) identified a
C-to-T transition in the VDR gene, resulting in a gln149-to-ter
(Q149X) substitution in the hinge region of the protein. The child
was born of consanguineous parents. Functional expression analyses
showed that the Q149X mutant receptor was unable to induce
transcription of the osteocalcin hormone gene response element at
low levels of vitamin D.
.0007 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, ARG271LEU]
In a child of Middle Eastern origin with vitamin D-dependent
rickets type II (277440), Kristjansson et al. (1993) identified a
G-to-T transversion in the VDR gene, resulting in an arg271-to-leu
(R271L) substitution in the steroid-binding domain of the receptor.
Functional expression studies showed that although the R271L
mutation was unable to induce transcription of the osteocalcin
hormone gene response element at low levels of vitamin D, it showed
normal transcription responses in the presence of 1,000-fold higher
vitamin D concentrations than needed for the wildtype receptor.
This showed that arginine-271 directly affects the affinity of VDR
for its ligand, and its conversion to leucine decreases its
affinity for vitamin D by a factor of 1,000. Arginine-271 is
located immediately 3-prime to a 30-amino acid segment that is
conserved among members of the steroid/thyroid/retinoid hormone
receptor superfamily.
.0008 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, GLY46ASP ]
In a Saudi Arabian child with vitamin D-resistant rickets type
II (277440) with consanguineous parents, Lin et al. (1996)
identified a G-to-A transition in exon 2 of the VDR gene, resulting
in a gly46-to-asp (G46D) substitution. Functional expression
studies showed that the mutant receptor displayed normal binding
affinity for 1,25-(OH)2D3, but had reduced affinity for DNA
binding. The mutant VDR was unable to activate gene transcription
in cells treated with up to 100 nmol/L of 1,25-(OH)2D3. Thus this
mutation, which occurs in the first zinc finger of the DNA-binding
domain of the receptor, blocks 1,25-(OH)2D3 action.
.0009 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, HIS305GLN]
Van Maldergem et al. (1996) reported an 8.5-year-old Turkish
boy, born of first-cousin parents, who had 3 different disorders:
congenital lipoatrophic diabetes (269700), persistent Mullerian
ducts (261550), and vitamin D-dependent rickets type II (277440).
In this boy, Malloy et al. (1997) identified a homozygous mutation
in the VDR gene, resulting in a his305-to-gln (H305Q) substitution
in the ligand-binding domain of the vitamin D receptor. The
mutation caused hereditary vitamin D-resistant rickets due to
decreased affinity for 1,25(OH)2D3. The disorder could be
effectively treated with extremely high doses of hormone. As
pictured by Van Maldergem et al. (1996) in their Figure 2, the
patient did not have alopecia but was hirsute, with hypertrichosis
of the face and acanthosis nigricans and pachydermia in the
axillae. The hands suggested acrogeria, and in general the patient
had a prematurely aged appearance.
.0010 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, ILE314SER ]
In a patient with vitamin D-dependent rickets type II (277440),
Whitfield et al. (1996) identified a mutation in the VDR gene,
resulting in an ile314-to-ser (I314S) substitution in the
hormone-binding domain of the protein. The mutation caused
decreased 1,25-(OH)2D3-dependent transactivation of the VDR and
impaired heterodimeric interaction with the retinoid X receptor
(RXR; 180245). However, the transactivation ability of the I314S
mutant
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receptor could be partially restored by providing excess
1,25-(OH)2D3; clinically, the patient had a nearly complete
response to pharmacologic doses of a vitamin D derivative.
.0011 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, ARG391CYS]
In a patient with vitamin D-dependent rickets type II (277440),
Whitfield et al. (1996) identified a mutation in the VDR gene,
resulting in an arg391-to-cys (R391C) substitution in the
hormone-binding domain of the protein. The mutation caused
decreased 1,25-(OH)2D3-dependent transactivation of the VDR and
impaired heterodimeric interaction with the retinoid X receptor
(RXR; 180245). The patient responded only partially to
pharmacologic doses of a vitamin D derivative.
.0012 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, ARG30TER]
In affected patients from a Brazilian family with vitamin
D-dependent rickets type II with alopecia (277440), Mechica et al.
(1997) identified a homozygous 88C-T transition in exon 2 of the
VDR gene, resulting in an arg30-to-ter (R30X) substitution in the
first zinc finger of the DNA-binding domain, truncating the VDR by
397 residues. The mutation occurred at a CpG dinucleotide. The
propositus, a 12-year-old boy born to first-cousin parents, had
early-onset rickets, total alopecia, convulsions, hypocalcemia,
secondary hyperparathyroidism, and elevated 1,25-dihydroxyvitamin
D3 serum levels. His younger sister also developed clinical and
biochemical features of the disorder at 1 month of age but died at
4 years of age.
Zhu et al. (1998) described a C-to-T transition at nucleotide
218 (as opposed to nucleotide 88 cited by Mechica et al., 1997) of
the VDR cDNA of a French Canadian boy with vitamin D-dependent
rickets type II born to nonconsanguineous parents. The single-base
substitution changed the codon for arginine (CGA) to an opal stop
codon (TGA), resulting in the truncation of the VDR protein at
amino acid 30. The result was truncation of 398 amino acids
including most of the zinc fingers as well as the entire
ligand-binding domain. Both parents were heterozygous for the
mutant allele. The child showed early-onset rickets, hypocalcemia,
secondary hyperparathyroidism, and elevated 1,25-dihydroxyvitamin D
levels as well as total alopecia. (The other stop codons are
referred to as amber (TAG) and ochre (TAA). See 141900.0312 for an
account of the history of this colorful system of designation.)
.0013 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, 1-BP DEL, 366C
]
In a patient with vitamin D-dependent rickets type II with
alopecia (277440), Miller et al. (2001) identified compound
heterozygosity for 2 mutations in the VDR gene: a 1-bp deletion
(366delC) in exon 4, resulting in premature termination, and a
985G-A transition in exon 8, resulting in a glu329-to-lys (E329K;
601769.0014) substitution. Miller et al. (2001) characterized the
alopecia associated with the disorder as clinically and
pathologically indistinguishable from that seen in generalized
atrichia with papular lesions (209500).
.0014 VITAMIN D-DEPENDENT RICKETS, TYPE II [VDR, GLU329LYS ]
See 601769.0013 and Miller et al. (2001).
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CONTRIBUTORS
Patricia A. Hartz - updated : 1/25/2007 John A. Phillips, III -
updated : 10/19/2006 Marla J. F. O'Neill - updated : 10/17/2006
Cassandra L. Kniffin - updated : 9/28/2006 Paul J. Converse -
updated : 9/1/2006 Paul J. Converse - updated : 4/12/2006 Patricia
A. Hartz - updated : 4/10/2006 Paul J. Converse - updated :
1/6/2006 Victor A. McKusick - updated : 10/14/2005 Cassandra L.
Kniffin - updated : 9/7/2005 Cassandra L. Kniffin - reorganized :
8/23/2005 John A. Phillips, III - updated : 7/15/2005 Marla J. F.
O'Neill - updated : 5/16/2005 Stylianos E. Antonarakis - updated :
11/24/2004 John A. Phillips, III - updated : 10/14/2004 Marla J. F.
O'Neill - updated : 10/1/2004 Victor A. McKusick - updated :
2/26/2004 Gary A. Bellus - updated : 5/12/2003 Victor A. McKusick -
updated : 8/9/2002 Ada Hamosh - updated : 5/28/2002 John A.
Phillips, III - updated : 7/11/2001 John A. Phillips, III - updated
: 7/2/2001 John A. Phillips, III - updated : 11/16/2000 John A.
Phillips, III - updated : 3/20/2000 Wilson H. Y. Lo - updated :
2/10/2000 Wilson H. Y. Lo - updated : 6/16/1999 Paul Brennan -
updated : 2/18/1999 John A. Phillips, III - updated : 1/8/1999
Victor A. McKusick - updated : 7/7/1998 John A. Phillips, III -
updated : 6/24/1998 John A. Phillips, III - updated : 3/18/1998
John A. Phillips, III - updated : 10/6/1997 Victor A. McKusick -
updated : 9/19/1997 Victor A. McKusick - updated : 9/2/1997 John A.
Phillips, III - updated : 8/26/1997 Victor A. McKusick - updated :
7/31/1997 John A. Phillips, III - updated : 1/8/1997
CREATION DATE
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Victor A. McKusick : 4/21/1997
EDIT HISTORY
mgross : 1/25/2007 alopez : 10/19/2006 wwang : 10/18/2006 terry
: 10/17/2006 wwang : 10/2/2006 ckniffin : 9/28/2006 mgross :
9/27/2006 mgross : 9/27/2006 terry : 9/1/2006 carol : 5/23/2006
wwang : 5/12/2006 mgross : 4/12/2006 mgross : 4/12/2006 mgross :
4/12/2006 terry : 4/10/2006 mgross : 1/6/2006 alopez : 10/17/2005
terry : 10/14/2005 wwang : 9/23/2005 wwang : 9/19/2005 ckniffin :
9/7/2005 carol : 8/23/2005 ckniffin : 8/15/2005 alopez : 7/15/2005
wwang : 5/18/2005 terry : 5/16/2005 carol : 1/25/2005 mgross :
11/24/2004 alopez : 10/14/2004 carol : 10/1/2004 tkritzer :
2/26/2004 alopez : 5/16/2003 alopez : 5/16/2003 alopez : 5/12/2003
alopez : 5/12/2003 alopez : 5/12/2003 tkritzer : 8/15/2002 tkritzer
: 8/13/2002 terry : 8/9/2002 alopez : 5/29/2002 terry : 5/28/2002
alopez : 7/11/2001 cwells : 7/3/2001 cwells : 7/2/2001 alopez :
1/25/2001 terry : 11/16/2000 mgross : 4/19/2000 terry : 3/20/2000
carol : 2/14/2000 carol : 2/14/2000
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yemi : 2/11/2000 yemi : 2/10/2000 carol : 12/6/1999 carol :
6/16/1999 alopez : 5/26/1999 alopez : 2/18/1999 alopez : 1/8/1999
dkim : 12/10/1998 terry : 7/14/1998 carol : 7/10/1998 terry :
7/7/1998 dholmes : 6/29/1998 dholmes : 6/24/1998 psherman :
3/19/1998 psherman : 3/18/1998 jenny : 11/26/1997 jenny :
11/17/1997 jenny : 10/22/1997 terry : 9/19/1997 mark : 9/9/1997
terry : 9/2/1997 terry : 8/5/1997 terry : 7/31/1997 alopez :
7/10/1997 joanna : 6/5/1997 jenny : 6/3/1997 jenny : 5/28/1997
jenny : 5/27/1997 mark : 5/2/1997 mark : 4/21/1997 jenny :
4/21/1997
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