1 Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and 2 Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington, District of Columbia 20007
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ABSTRACT |
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The heterotrimeric G protein Gs is required
for hormone-stimulated intracellular cAMP generation because it couples
hormone receptors to the enzyme adenylyl cyclase. Hormones that
activate Gs in the kidney include parathyroid hormone,
glucagon, calcitonin, and vasopressin. Recently, it has been
demonstrated that the Gs gene is imprinted in a
tissue-specific manner, leading to preferential expression of
Gs
from the maternal allele in some tissues. In the
kidney, Gs
is imprinted in the proximal tubule but not
in more distal nephron segments, such as the thick ascending limb or
collecting duct. This most likely explains why in both humans and mice
heterozygous mutations in the maternal allele lead to parathyroid
hormone resistance in the proximal tubule whereas mutations in the
paternal allele do not. In contrast, heterozygous mutations have little
effect on vasopressin action in the collecting ducts. In mice with
heterozygous null Gs
mutations (both those with
mutations on the maternal or paternal allele), expression of the
Na-K-2Cl cotransporter was decreased in the thick ascending limb,
suggesting that its expression is regulated by cAMP. The Gs
genes also generate alternative, oppositely imprinted
transcripts encoding XL
s, a Gs
isoform with a long
NH2-terminal extension, and NESP55, a chromogranin-like
neurosecretory protein. The role, if any, of these proteins in renal
physiology is unknown.
genomic imprinting; Albright hereditary osteodystrophy; adenosine 3',5'-cyclic monophosphate; pseudohypoparathyroidism; parathyroid hormone
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INTRODUCTION |
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MANY HORMONES THAT REGULATE water and electrolyte
transport in the kidney, such as parathyroid hormone (PTH),
vasopressin, glucagon, and calcitonin, share a common signal
transduction mechanism whereby receptor binding leads to increased
intracellular concentrations of cAMP. The components necessary for
hormone-stimulated cAMP generation are the receptor, the heterotrimeric
G protein Gs, and adenylyl cyclase, which catalyzes the
conversion of ATP to cAMP. The receptor is specific for each hormone
whereas Gs and adenylyl cyclase are components common to
all signaling pathways that lead to increased cAMP. The physiological
responses to increased intracellular cAMP are cell-type specific. For
example, PTH-stimulated cAMP generation in the proximal tubule leads to
decreased phosphate reabsorption and probably increased
1-hydroxylation of 25-hydroxyvitamin D whereas
vasopressin-stimulated cAMP generation in the collecting ducts leads to
increased water permeability.
Each heterotrimeric G protein is composed of an -,
-, and
-subunit (for reviews, see Refs. 65, 70). The
- and
-subunits form a tightly but noncovalently bound dimer. G proteins are identified by their specific
-subunits, which bind guanine nucleotides and are
important in both receptor and effector coupling. The
-subunit of
the G protein Gs is ubiquitously expressed and couples
receptors to the stimulation of adenylyl cyclase and the opening of
specific ion channels (53). There are at least nine isoforms of
adenylyl cyclase. All bind to and are stimulated by Gs
but differ in their regulation by other intracellular compounds, such
as
, calcium, and protein kinases A and C (64).
The genes encoding Gs are single copy in human
(GNAS1) and mouse (Gnas). GNAS1 is
located at 20q13 (28, 29, 50) whereas Gnas is located in distal
chromosome 2 within a region syntenic to human 20q13 (10, 59). It has
recently been recognized that these genes are subject to genomic
imprinting and generate multiple transcripts, some which are expressed
only from the maternal allele and others that are expressed only from
the paternal allele (31, 32, 60, 75). In mice (and probably in humans)
Gs
is expressed primarily from the maternal allele in
some tissues but is biallelically expressed in other tissues (75).
Genomic imprinting is an epigenetic phenomenon affecting a small number
of autosomal genes, which leads to preferential expression of either
the maternal or paternal allele (for reviews, see Refs. 2 and 14). For
example, the Igf2 and Snrpn genes are only transcriptionally active on the paternal allele whereas the
Igf2r and H19 genes are only active on the maternal
allele. Some genes (e.g., Ube3a, Igf2) are imprinted in
a tissue-specific manner (1, 16), with a single allele active in some
tissues and both alleles active in other tissues. Within imprinted
genes are regions in which the maternal and paternal alleles are
differentially methylated, which appear to be critical for both the
initiation and maintenance of imprinting (14). Generally, the
differential methylation patterns that maintain imprinting are erased
in the primordial germ cell. Differential methylation which is
reestablished in either the male or female gametes is presumed to
represent the methylation imprint mark that distinguishes the maternal
and paternal alleles in the offspring. Other differentially methylated regions are established later during postimplantation development. Genetic or epigenetic abnormalities involving imprinted genes have been
implicated in several congenital disorders, such as the
Angelman/Prader-Willi and Beckwith-Wiedeman syndromes, and in
carcinogenesis. In this review we will summarize the evidence that
GNAS1 and Gnas are imprinted genes and that
Gs is imprinted in a tissue-specific manner and discuss
the physiological consequences of tissue-specific imprinting of
Gs
in the nephron.
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THE GS![]() |
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Albright Hereditary Osteodystrophy (AHO)
The first evidence for imprinting of GNAS1 was provided by the unusual pattern of inheritance of AHO, a human disorder characterized by short stature, obesity, brachydactyly, subcutaneous ossifications, and mental defects and associated with null GNAS1 mutations (70). AHO patients present with either the somatic features of AHO alone (termed pseudopseudohypoparathyroidism [PPHP]) or AHO plus resistance to multiple hormones that activate Gs-coupled pathways in their target organs (termed pseudohypoparathyroidism type Ia [PHP-Ia]). PHP-Ia patients, who are resistant to PTH, have a markedly reduced urinary cAMP response to administered PTH (11) whereas in PPHP patients, who have normal serum calcium and PTH levels, the urinary cAMP response is normal (49). The defect was localized to Gs on the basis of the fact that Gs levels are decreased by ~50% in membranes isolated from various easily accessible cell types (e.g., erythrocytes, skin fibroblasts, platelets, and transformed lymphoblasts) (5, 20-22, 47, 48). In these tissues GsBoth PHP-Ia and PPHP patients have similar decreases in
Gs expression in accessible tissues (49) and identical
GNAS1 mutations (57, 70, 72). How identical GNAS1
mutations lead to multihormone resistance in some patients (PHP-Ia) but
not in others (PPHP) remained a mystery until it was noted that
maternal transmission of AHO leads to offspring with PHP-Ia whereas
paternal transmission leads to offspring with PPHP (15, 74), suggesting
that GNAS1 might be imprinted. If the GNAS1 paternal
allele is poorly expressed due to imprinting in a hormone target tissue
(such as the proximal tubule, the major renal target for PTH), then a
null mutation in the active maternal allele would markedly reduce
Gs
expression and lead to hormone resistance (PHP-Ia).
In contrast, a null mutation in the relatively inactive paternal allele
should have little effect on Gs
expression and therefore
little effect on hormone action (PPHP). This model is supported by the
fact that the urinary cAMP response to exogenous PTH is markedly
reduced in PHP-Ia patients but normal in PPHP patients (49). Although
this model has been confirmed in mice (see below), it has yet to be
definitively proven in humans, and in fact Gs
has been
shown to be expressed from both alleles in various human fetal tissues
(7, 31, 32). This most likely reflects the fact that the imprinting is
tissue specific, as there is no evidence for imprinting in various
accessible tissues such as blood cells and fibroblasts, where
Gs
expression is equally decreased by 50% in both
PHP-Ia and PPHP patients. Imprinting of Gs
in humans can
only be established by examining specific hormonal target tissues, such
as the renal proximal tubule.
Further evidence for imprinting of Gs in humans is
provided by a study that examined four kindreds affected with PHP type Ib (PHP-Ib) (39). PHP-Ib is characterized by PTH resistance in the
absence of AHO or resistance to other hormones. Like PHP-Ia patients,
PHP-Ib patients have a markedly reduced urinary cAMP response to PTH,
localizing the defect to a signaling component including, or upstream
of, adenylyl cyclase (46, 63). Unlike PHP-Ia, Gs levels are
normal in easily accessible tissues, ruling out a mutation involving
the Gs
coding region. Several lines of evidence rule out
defects in the PTH receptor as the cause of PHP-Ib (4, 25, 26, 38, 61).
In four PHP-Ib kindreds PTH resistance was only evident in individuals
who inherited the trait from their mother (39), a pattern similar to
the inheritance pattern of PTH resistance in PHP-Ia. Moreover, linkage
analysis performed on these four kindreds mapped the disease gene to
20q13, in the vicinity of GNAS1. One possible explanation for
PTH resistance in these kindreds is an imprinting defect that impairs
the switching of the paternal to maternal imprint in the female
germline, leading to offspring with a paternal imprint in both alleles.
This would drastically reduce Gs
expression in the renal
proximal tubules, leading to PTH resistance, but should not affect
Gs
expression in other tissues where Gs
is equally expressed from the maternal and paternal alleles. Such
imprinting defects have been identified in the SNRPN gene,
leading to Prader-Willi and Angelman's syndromes (34).
The Gs-Knockout (GsKO) Mouse Model
To directly determine the imprinting status of Gs in
specific tissues, we measured the levels of Gs
expression in m
/+ and +/p
mice relative to those in
normal mice. In tissues where the paternal allele is poorly expressed,
Gs
expression should be markedly reduced in m
/+
mice and normal in +/p
mice, whereas in tissues where
Gs
is not imprinted, Gs
expression should
be equally decreased by ~50% in both m
/+ and +/p
mice.
Gs
mRNA and protein expression in renal proximal tubules
is markedly reduced in m
/+ mice and normal in +/p
mice,
consistent with imprinting of the Gnas paternal allele in this
tissue. In contrast, Gs
expression in the renal inner
medulla (which consists primarily of collecting tubules) and outer
medulla [which consists primarily of thick ascending limbs
(TAL)] (43) was equally reduced by ~50% in both m
/+ and
+/p
mice (19, 75), consistent with lack of imprinting in these
more distal portions of the nephron. In contrast to the results of
Williamson and colleagues (73), we did not see a difference in
Gnas expression between these two groups of mice in renal
glomeruli, suggesting lack of imprinting in the glomerulus. Gs
is also imprinted in some tissues outside of the
kidney, such as brown and white adipose tissue, but is not imprinted in
others, such as lung and skeletal muscle (Yu and Weinstein, unpublished observations). These results confirm that in mice Gs
is
imprinted in a tissue-specific manner and, specifically, that
Gs
is imprinted in the proximal tubules but not in other
portions of the nephron.
Alternative GNAS1 and Gnas Transcripts are Oppositely Imprinted
GNAS1 was initially defined by the 13 exons that comprise the coding region for Gs
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If XLs plays a major role in human physiology, then PPHP patients
(in whom XL
s expression would be disrupted by mutations in the
paternal allele) should have clinical manifestations that are not also
found in PHP-Ia patients (in whom XL
s expression would be
unaffected). In fact, this is not the case, suggesting that XL
s
might not be critical in humans or that a closely related protein
performs its function in PPHP patients. Similarly, several lines of
evidence suggest that NESP55 might not be critical for human physiology
or development. PHP-Ia patients with missense mutations within the
Gs
encoding region (54, 62, 68, 69) would likely have
normal NESP55 expression because these mutations would not disrupt the
NESP55 coding region or NESP55 mRNA expression. In contrast, early
splice site and premature termination mutations would decrease NESP55
mRNA expression, similar to their effect on Gs
mRNA
expression (71, 72). In fact, there is little correlation between the
type of mutation present and the clinical presentation of PHP-Ia
patients. Also, the fact that exon 1 mutations (which should only
disrupt Gs
expression) and more downstream mutations
(which should disrupt all GNAS1 gene products) produce similar
phenotypes suggests that most or all of the manifestations of AHO
result from decreased Gs
expression (57). Further
studies are required to define the roles of XL
s and NESP55 in human physiology.
In contrast to humans, disruption of the maternal or paternal
Gnas allele in mice leads to distinct phenotypes with severe manifestations, including early lethality. The distinct phenotypes of
m/+ and +/p
mice could be due to the disruption of
paternally and maternally expressed transcripts resulting from our exon
2 insertion. The role for disruption of alternative Gnas
transcripts in the m
/+ and +/p
phenotypes is further
supported by the observation that these developmental and lethal
phenotypes are absent in mice with a Gnas exon 1 deletion,
which should only disrupt the Gs
transcript (W. F. Schwindinger and M. A. Levine, personal communication).
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IMPLICATIONS OF GS![]() |
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The imprinting status of Gs in the renal proximal
tubule, TAL, and collecting ducts and the resulting physiological
effects in AHO patients and GsKO mice are summarized in Fig.
2.
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Renal Responses to PTH
PTH-stimulated cAMP generation in the proximal tubule leads to decreased phosphate reabsorption and increased synthesis of 1,25 dihydroxyvitamin D. In PHP-Ia patients, PTH-stimulated cAMP generation is markedly reduced, leading to decreased phosphate excretion and synthesis of 1,25 dihydroxyvitamin D. Decreased 1,25 dihydroxyvitamin D leads to hypocalcemia, because it is required for intestinal calcium absorption and calcium release from bone. These physiological abnormalities result in hypocalcemia, hyperphosphatemia, and elevated serum PTH, the clinical hallmarks of PTH resistance. In contrast, PTH-stimulated cAMP generation is normal in PPHP patients, and these patients show no evidence for PTH resistance. Until recently it was unclear how maternal inheritance of GNAS1 mutations leads to PTH resistance (PHP-Ia) whereas paternal inheritance does not (PPHP). Similarly, we have recently shown in the GsKO mouse model that mPTH also acts on more distal portions of the nephron to increase
calcium reabsorption, and thus patients with primary hypoparathyroidism (deficient PTH secretion) are prone to hypercalciuria. In contrast, this action of PTH remains intact in PHP-Ia, and therefore it is
uncommon for these patients to develop hypercalciuria (66). One
possible explanation for this discrepancy is that Gs is
not imprinted in the more distal portions of the nephron (e.g., TAL) where PTH affects calcium reabsorption. The predicted half-normal cAMP
response to PTH in this portion of the nephron may be sufficient to
produce a maximal physiological response, as has been shown for
responses to glucagon and isoproterenol in PHP-Ia patients (6, 8, 46).
It is also possible that the action of PTH to increase calcium
reabsorption is maintained in PHP-Ia because this response is not
dependent on cAMP (24).
Sodium Transport in the TAL
Both GsA decrease in NaCl transport due to decreased Na-K-2Cl cotransporter
abundance would be predicted to result in decreased countercurrent multiplication by the loop of Henle and decreased medullary solute concentrations. Consistent with this hypothesis, the urinary
concentrating ability measured 1 h after intraperitoneal administration
of vasopressin analog was significantly reduced by 28% in m/+
mice (19). One study in PHP-Ia patients found no significant decrease
in urinary concentrating ability in response to acute intravenous
vasopressin infusion, although only three patients were examined in
this study (56). The decreased urinary concentrating ability observed
in heterozygous GsKO mice could also be the result of vasopressin resistance in the collecting duct, although this possibility is less
likely (see Vasopressin Responses in the Collecting
Duct).
After water deprivation for 48 h, which leads to a maximal increase in circulating vasopressin levels, the abundance of the Na-K-2Cl cotransporter in the TAL was no longer different between mutant and wild-type animals (19). Consistent with this finding, no difference in maximal urinary concentrating ability could be detected after 48 h of water deprivation (19, 75). The most likely explanation for these observations is that chronic exposure to maximal vasopressin concentrations results in cAMP levels within the TAL of mutant mice that exceed those required for maximal stimulation of cotransporter expression.
Vasopressin Responses in the Collecting Duct
Both PHP-Ia patients (23, 56) and mIt is interesting that, unlike in the IMCD, AQP2 expression is
decreased in the CCD of both m/+ and +/p
mice. Decreased AQP2 expression might reflect lower basal levels of cAMP in the CCD
because vasopressin-stimulated cAMP generation has been shown to vary
between different portions of the collecting duct (51). After 48 h of
water deprivation there were no longer differences in AQP2 expression
in the CCD between mutant and normal mice (C. A. Ecelbarger and M. Knepper, unpublished observations), suggesting that, as in the TAL,
maximal stimulation leads to cAMP levels that exceed the threshold
required for a maximal downstream response (e.g., AQP2 expression). The
similar effects in the collecting ducts of m
/+ and +/p
mice are consistent with lack of Gs
imprinting in the
CCD and IMCD. It is unlikely that the observed decrease in AQP2
expression in the CCD leads to polyuria because the normal osmotic
water permeability in the collecting ducts far exceeds that required to
generate a maximally concentrated urine (13).
Whether there are defects in AQP2 translocation in response to vasopressin in GsKO mice has not been examined, although it is known that the levels of cAMP achieved by acute vasopressin administration greatly exceed those required for maximal osmotic water permeability (12). The lack of apparent vasopressin resistance in the collecting ducts of PHP-Ia patients and GsKO mice probably reflects both the large excess of cAMP in the collecting ducts relative to the amount required for downstream cellular responses and the excess capacity for osmotic water permeability in the collecting ducts relative to that required to produce a fully concentrated urine.
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FOOTNOTES |
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Address for reprint requests and other correspondence: L. S. Weinstein, Metabolic Diseases Branch, NIDDK/NIH, Bld. 10, Rm 8C101, Bethesda MD 20892-1752 (E-mail: leew{at}amb.niddk.nih.gov).
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