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Mechanisms of Disease: mutations of G proteins
and G-protein-coupled receptors in endocrine
diseases
Andrea G Lania, Giovanna Mantovani and Anna Spada*
INTRODUCTION
S U M M A RY
G proteins and G-protein-coupled receptors (GPCRs) mediate the effects
of a number of hormones. Genes that encode these molecules are subject
to loss-of function or gain-of-function mutations that result in endocrine
disorders. Loss-of-function mutations prevent signaling in response
to the corresponding agonist and cause resistance to hormone actions,
which mimics hormone deficiency. Gain-of-function mutations lead to
constitutive, agonist-independent activation of signaling, which mimics
hormone excess. Disease-causing mutations of GPCRs have been identified
in patients with various disorders of the pituitary–thyroid, pituitary–
gonadal and pituitary–adrenal axes, and in those with abnormalities
in food intake, growth, water balance and mineral-ion turnover. The
only mutational changes in G proteins unequivocally associated with
endocrine disorders occur in GNAS (guanine nucleotide-binding protein
G-stimulatory subunit α, or Gsα). Heterozygous loss-of-function mutations
of GNAS in the active, maternal allele cause resistance to hormones that
act through Gsα-coupled GPCRs, whereas somatic gain-of-function
mutations cause proliferation of endocrine cells that recognize cyclic AMP
as a mitogen. The study of mutations in G proteins and GPCRs has already
had major implications for understanding the molecular basis of rare
endocrine diseases, as well as susceptibility to multifactorial disorders that
are associated with polymorphisms in these genes.
KEYWORDS cyclic AMP, endocrine diseases, G protein, G-protein-coupled
receptor, GSP oncogene
REVIEW CRITERIA
We searched PubMed for publications using different combinations of the following
search terms: “endocrine disease”, “GPCR”, “G protein”, “GNAS”, “gene mutation”,
“pituitary–thyroid axis”, “thyrotropin-releasing hormone receptor”, “thyroidstimulating hormone receptor”, “pituitary–gonadal axis”, “G-protein-coupled
receptor 54”, “gonadotropin-releasing hormone receptor”, “gonadotropin hormone
receptor”, “pituitary–adrenal axis”, “adrenocorticotropic hormone receptor”,
“melanocortin 4 receptor”, “growth-hormone-releasing hormone receptor”,
“vasopressin V2 receptor”, “diabetes insipidus”, “SIADH”, “calcium-sensing receptor”,
and “parathyroid hormone receptor”. All selected papers were English-language, fulltext articles. A number of references were not included because of space restrictions.
AG Lania is a Research Associate, G Mantovani is a Postdoctoral Fellow and
A Spada is a Professor of Endocrinology at the Endocrine Unit, Department
of Medical Sciences, University of Milan, Fondazione IRCCS Ospedale
Maggiore, Policlinico, Mangiagalli, Regina Elena, Milan, Italy.
Advances in understanding the molecular biology
of signal transduction have had a considerable
impact on several aspects of basic research and
clinical medicine. G-protein-coupled receptors
(GPCRs) are one of the major classes of signaling
proteins; they mediate numerous physiologic
processes of relevance to endocrinology. In the
past few years, studies have identified genes that
code for G proteins and GPCRs as loci for lossof-function and gain-of-function mutations
that result in human diseases. This article will
briefly describe genetic alterations of G proteins
and GPCRs that lead to endocrine diseases
(Tables 1 and 2).
G-PROTEIN-COUPLED RECEPTORS
GPCRs constitute one of the largest classes of
proteins (encoded by more than 800 genes in
the human genome). GPCRs are responsible for
signal transduction1 and mediate the effects of
endogenous ligands, such as neurotransmitters,
neuropeptides, hormones and ions, as well as
sensory stimuli, such as light, odorants and gustatory compounds. There are, moreover, many
GPCRs (so-called orphan GPCRs) for which the
endogenous agonist is still unknown. GPCRs
share significant structural homology, and are
predicted to exhibit a common, ‘serpentine’ structure: seven hydrophobic regions that form transmembrane α-helices, connected by alternating
extracellular and intracellular loops2 (Figure 1).
A general model for GPCR activity has postulated
that GPCRs are in equilibrium between an active
and an inactive state, and that interaction with
a GPCR agonist elicits or stabilizes a conformational change in the GPCR, which favors binding
to a G protein (or to multiple G proteins) and
signal generation inside the cell.3
Correspondence
*Endocrine Unit, Department of Medical Sciences, University of Milan, Fondazione IRCCS Ospedale
Maggiore, Policlinico, Mangiagalli, Regina Elena, Via Francesco Sforza 35, 20122 Milan, Italy
[email protected]
Mutations in genes that encode GPCRs can cause
losses or gains of function.4 Loss-of-function
(inactivating) mutations prevent signaling in
Received 27 February 2006 Accepted 10 July 2006
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MAIN FEATURES OF ENDOCRINE
DISEASES CAUSED BY GPCR MUTATIONS
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Table 1 Mutations in genes for GPCRs and G proteins that lead to disorders in pituitary axes.
Gene
Mutation
Disease
OMIM#
Pituitary–thyroid axis
TRHR
Inactivating, germline
Isolated central hypothyroidism
TSHa
188545
TSHR
Inactivating, germline
Activating, somatic
Activating, germline
Resistance to
Toxic thyroid adenomab
Hereditary toxic thyroid hyperplasiab
Familial gestational hyperthyroiditisb
275200
603372
609152
603373
GNAS
Inactivating, germline
Activating, somatic
Resistance to TSH in PHP1aa
Toxic thyroid adenomab
Thyroid adenoma in MASb
Thyroid carcinoma
103580
603372
174800
NA
Pituitary–gonadal axis
KISS1R
Inactivating, germline
Hypogonadotropic hypogonadism
146110
GNRHR
Inactivating, germline
Familial idiopathic hypogonadotropic hypogonadism
146110
LHCGR
Inactivating, germline
Activating, germline
Male pseudohermaphroditisma
Hypergonadotropic hypogonadisma
Male-limited pituitary-independent precocious pubertyb
152790
152790
176410
FSHR
Inactivating, germline
Activating, germline
Hypergonadotropic hypogonadism with amenorrheaa
Ovarian hyperstimulation syndrome
238320
136435
GNAS
Inactivating, germline
Activating, somatic
Resistance to LH and FSH in PHP1aa
Precocious puberty in MASb
Leydig cell tumor
Ovarian granulosa cell tumors
103580
174800
NA
NA
Pituitary–adrenal axis
MC2R
Inactivating, germline
Familial glucocorticoid deficiencya
202200
GIPR, LHCGR,
or β-adrenergic
receptor genes
Aberrant expression
Cushing’s syndrome
219080
GNAS
Activating, somatic
Adrenal adenoma, bilateral adrenal hyperplasia
NA
aPhenotype
of hormone deficiency associated with normal or high serum levels of biologically active hormone and absence of
autoimmunity. bPhenotype of hormone excess associated with low or undetectable serum levels of corresponding hormone
and absence of autoimmunity. Abbreviations: FSH, follicle-stimulating hormone; FSHR, follicle-stimulating hormone receptor;
GIPR, gastric inhibitory polypeptide receptor; GNAS, guanine nucleotide-binding protein G-stimulatory subunit α; GNRHR,
gonodatropin-releasing hormone receptor; GPCR, G-protein-coupled receptor; KISS1R, kisspeptin 1 receptor (previously termed
G-protein-coupled receptor 54); LH, luteinizing hormone; LHCGR, luteinizing hormone and choriogonadotropin receptor;
MAS, McCune–Albright syndrome; MC2R, melanocortin 2 receptor; NA, not available; OMIM#, Online Mendelian Inheritance in Man
accession number; PHP1a, pseudohypoparathyroidism type 1a; TRHR, TSH-releasing hormone receptor; TSHR, TSH receptor.
response to the corresponding agonist, and
cause resistance to hormone action, which
mimics hormone deficiency.4 Clinically significant impairment of signal transduction generally requires loss of function of both alleles
and, therefore, most endocrine diseases caused
by inactivating GPCR mutations are recessive,
though several exceptions have been reported.
These mutations can be missense, nonsense
or frameshift mutations that result in absent
or functionally defective proteins, which exhibit
abnormal targeting to the cell membrane, trafficking or degradation.5 They may involve
any portion of the receptor, particularly the
membrane-spanning helices.
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Gain-of-function mutations in GPCRs lead to
constitutive, agonist-independent activation of
signaling, which mimics states of hormone excess.
These activating mutations are almost always
missense mutations that are able to disrupt the
normal inhibitory constraints that maintain
the receptor in its inactive conformation. Most
endocrine diseases caused by activating GPCR
mutations are inherited in a dominant manner.
Interestingly, activating mutations in GPCRs that
are coupled to the cyclic AMP (cAMP)-dependent
pathway (e.g. the TSH receptor, TSH-R) are also
associated with proliferative effects.
The phenotype caused by inactivating or
activating GPCR mutations depends on the
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Table 2 Mutations in genes for GPCRs and G proteins that lead to disorders in weight, growth, water
balance and mineral-ion turnover.
Disorder
Gene
Mutation
Disease
OMIM#
Obesity
MC4R
Inactivating, germline
Obesity
155541
GH and growth
GHRHR
GHSR
GNAS
Inactivating, germline
Inactivating, germline
Inactivating, germline
Activating, somatic
Isolated GH deficiency
Short stature
Resistance to GHRH in PHP1aa
GH-secreting pituitary adenoma
GH-secreting pituitary adenoma in MAS
139191
601898
103580
139320
174800
Water balance
AVPR2
Inactivating, germline
Activating, germline
Nephrogenic diabetes insipidus type 1a
Nephrogenic syndrome of inappropriate
antidiuresisb
304800
300539
Mineral-ion
turnover
CASR
Inactivating, germline
Familial hypocalciuric hypercalcemia
(heterozygous)
Neonatal severe primary hyperparathyroidism
(homozygous)
Familial hypercalciuric hypocalcemia
Blomstrand chondrodysplasia
Jansen-type metaphyseal chondrodysplasiab
Resistance to PTH in PHP1aa
145980
PTHR1
GNAS
Activating, germline
Inactivating, germline
Activating, germline
Inactivating, germline
239200
146200
215045
156400
103580
aPhenotype
of hormone deficiency associated with normal-to-high serum levels of biologically active hormone and absence
of autoimmunity. bPhenotype of hormone excess associated with low or undetectable serum levels of the corresponding
hormone and absence of autoimmunity. Abbreviations: AVPR2, arginine vasopressin receptor 2; CASR, calcium-sensing
receptor; GH, growth hormone; GHRH, growth-hormone-releasing hormone; GHRHR, growth-hormone-releasing hormone
receptor; GHSR, ghrelin and GH secretagogue receptor; GNAS, guanine nucleotide-binding protein G-stimulatory protein
subunit α; GPCR, G-protein-coupled receptor; MAS, McCune–Albright syndrome; MC4R, melanocortin 4 receptor;
OMIM#, Online Mendelian Inheritance in Man accession number; PHP1a, pseudohypoparathyroidism type 1a;
PTH, parathyroid hormone; PTHR1, parathyroid hormone receptor 1.
specific receptor involved, the range of tissues
it is expressed in, and whether the mutation
occurs in germline (gamete) cells—and, therefore, affects every cell that expresses the gene—
or is somatic (present only in a subpopulation
of cells that express the gene) and leads to focal
manifestations of disease.
GPCR MUTATIONS AND THE
PITUITARY–THYROID AXIS
TSH-releasing hormone receptor
Central hypothyroidism is mostly caused by
tumors or infiltrative diseases of the hypothalamic–pituitary region. At present, only one
patient with a defect in TSH signaling caused by
resistance to the actions of TSH-releasing
hormone (TRH) has been described.6 In particular, this individual, who showed the typical
biochemical parameters of central hypothyroidism (low thyroid hormone and lownormal TSH levels) was a compound heterozygote
for two different loss-of-function mutations in
the TRH receptor gene (i.e. the patient had inherited a different mutation from each parent). In
this individual, the lack of TSH and prolactin
response to a TRH-stimulation test predicted
the loss-of-function mutations in TRHR. No
DECEMBER 2006 VOL 2 NO 12 LANIA ET AL.
gain-of-function mutations have been reported
so far.
TSH receptor
The TSH-R has a marked propensity toward
overactivity or underactivity, probably because
of molecular instability. Indeed, the large number
of different, naturally occurring TSHR mutations
provided an initial basis for characterization of the
protein domains required for TSH-R activation,
which were subsequently confirmed by in vitro
investigations. Germline, loss-of-function mutations induce either a partial or a complete resistance to TSH. The resultant disease phenotypes
range from mild, subclinical hypothyroidism, to
congenital, severe hypothyroidism, depending
on the type of mutation and the affected individual’s homozygous, compound heterozygous or
heterozygous status.4,7–9
Gain-of-function mutations can occur at the
somatic or germline level. The two somatic,
missense substitutions that were originally
found in toxic thyroid adenomas (Ala623Ile
and Asp619Gly) were the first naturally occurring activating mutations of a GPCR to be
associated with tumorigenesis.10 Since then,
several TSHR mutations, mostly located in the
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N terminus
GPCR
C terminus
γ
GDP
α
γ
β
β
α
GTP
Second messenger
Hormone
secretion
Gene transcription
Figure 1 Schematic representation of GPCRs and G proteins. GPCRs are
expressed on the cell surface and share a common, ‘serpentine’ structure
characterized by seven hydrophobic regions that form transmembrane
α-helices, which are connected by alternating extracellular and intracellular
loops. The interaction of an agonist with its binding site (which can be located
in the seven transmembrane domains or in the extracellular loops and
N terminus) elicits, or stabilizes, a conformational change in the receptor. This
conformational change allows a specific G protein to bind, and a signaling
cascade to be generated, inside the cell. The cytoplasmic loops are similar
among GPCRs. This similarity is consistent with the presence of a common
mechanism, by which hundreds of GPCRs activate only a few dozen
G proteins. The G proteins are composed of the α subunit, which is specific for
each G protein, and the common β and γ subunits. The GDP-bound
α subunit binds tightly to the β–γ complex and is inactive, whereas the GTPbound α subunit can dissociate from the β–γ complex and activate effector
proteins. Interaction of an agonist with a specific GPCR induces activation of
the G protein, by facilitating the exchange of GDP for GTP on the α subunit. The
duration of such dissociation is determined by the rate of α-subunit-mediated
hydrolysis of GTP. Signaling via second messengers can then lead to gene
transcription and hormone secretion. Abbreviations: α, β, γ, G-protein
subunits; GPCR, G-protein-coupled receptor.
should be screened for TSHR mutations, and
should be treated early and aggressively to avoid
tumor recurrence.
A particular mutation in the extracellular
N-terminal domain of the TSH-R (Lys183Arg)
confers an abnormally high sensitivity to human
chorionic gonadotropin (hCG) on this receptor,
which leads to a rare syndrome referred to
as familial gestational hyper thyroidism.13
Although some degree of thyroid stimulation
by hCG is frequently observed during the first
trimester of pregnancy, in a family with the
Lys183Arg mutation, a mother and daughter
(both heterozygous for this mutation) were
severely hyperthyroid only during each of
their pregnancies.13
GPCR MUTATIONS AND THE
PITUITARY–GONADAL AXIS
Kisspeptin 1 receptor
Gonadotropin-releasing hormone (GnRH)
is critical for normal secretion of folliclestimulating hormone (FSH) and luteinizing
hormone (LH), and for pubertal development
and reproduction. The evidence indicates that
at the onset of puberty, activation of GnRH
neurons (and consequently GnRH release from
the forebrain) is mediated by kisspeptin 1, the
endogenous ligand of the kisspeptin 1 receptor
(KiSS-1R, encoded by KISS1R, previously named
GPR54), which is expressed in GnRH neurons.
Loss-of-function KiSS-1R mutations cause
congenital hypogonadotropic hypogonadism in
both sexes, characterized by delayed puberty, low
sex steroid levels, and low-normal gonadotropin
levels that are responsive to GnRH.14
Gonadotropin-releasing hormone
receptor
third cytoplasmic loop or in the adjacent sixth
transmembrane segment, have been identified
in about 80% of toxic thyroid adenomas.9,11
These mutations confer constitutive activity
on the TSH-R, and result in TSH-independent
cAMP accumulation and consequent endocrine
hyperfunction, together with clonal expansion
of the mutated cell. When these same TSHR
substitutions occur in the germline, they cause
a rare form of hyperthyroidism characterized
by variable age of onset, goiter and absence of
autoimmunity, referred to as hereditary toxic
thyroid hyperplasia.12 Patients with familial or
congenital, nonautoimmune hyperthyroidism
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Several loss-of-function mutations of the GnRH
receptor, which can be present in either homozygous or compound heterozygous forms, have
been identified in patients with familial idiopathic hypogonadotropic hypogonadism.15,16
These mutations frequently cause reduced
expression of the GnRH receptor at the plasma
membrane, and its increased retention and/or
degradation in the endoplasmic reticulum.5
The disease affects males and females, and the
resulting phenotypes span a continuum between
complete and partial gonadotropic deficiency
(also termed ‘fertile eunuch’, in men). No gainof-function mutations of the GnRH receptor
have been reported.17
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Luteinizing hormone receptor
Loss-of-function and gain-of-function mutations have been identified in the LH receptor
(LHR) gene, LHCGR.18 Homozygous, lossof-function LHR mutations cause Leydig
cell hypoplasia or agenesis and a variable
phenotype—from complete male pseudohermaphroditism, characterized by XY genotype
with female external genitalia, high LH, normal
FSH and barely detectable testosterone levels that
are unresponsive to hCG treatment, to very mild
undervirilization.18,19 Affected females present
with a relatively mild phenotype, characterized
by amenorrhea with normal development of
primary and secondary sexual characteristics,
elevated LH, normal or elevated FSH and low
estradiol levels.18
Familial, male-limited, pituitary-independent
precocious puberty (also known as familial testotoxicosis) was the first-known example of an
inherited endocrine disease caused by a constitutively active GPCR (in this case, the LHR).20 The
disease is characterized by testicular enlargement
before 3–4 years of age, with high testosterone
and low gonadotropin levels. Asp578Gly substitution is the most common cause of familial
testotoxicosis in the US. Interestingly, Asp578His,
which occurs exclusively at the somatic level,
causes Leydig cell transformation and adenoma
formation.21 In females, activating LHR mutations do not seem to cause a recognizable phenotype, probably because of low LHR expression in
prepubertal ovaries.
Follicle-stimulating hormone receptor
Loss-of-function and gain-of-function mutations
have been identified in the FSH receptor (FSH-R)
gene, FSHR.18 Inactivating mutations have been
reported in females with hypergonadotropic
hypogonadism, primary or early-onset
secondary amenorrhea, variable development of
secondary sex characteristics and premature arrest
of follicular maturation.18,22 Affected males have
normal androgen production and reduced sperm
quality, but remain fertile. Despite the rarity of
FSH-R mutations, there is good correlation
between genotype and phenotype, and both these
factors should be considered when managing
these patients. Individuals with mutations
that cause mild phenotypes may still respond to
stimulation with high doses of FSH.18
To date, one activating mutation in FSHR has
been reported, in a hypophysectomized man
with persistent spermatogenesis in spite of
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undetectable gonadotropins.23 More recently,
substitutions in the serpentine domain of FSH-R
(Thr449Ile and Asp567Asn) that confer sensitivity to hCG have been reported in women with
recurrent ovarian hyperstimulation syndrome,
a complication that can occur following hCG
administration for in vitro fertilization.18,24
GPCR MUTATIONS AND ADRENAL
FUNCTION
Familial glucocorticoid deficiency is a rare,
autosomal recessive disease due to defective
functioning or trafficking of melanocortin 2
receptor (MC2-R, formerly known as adrenocorticotropic hormone [ACTH] receptor).
Approximately 25% of individuals with familial
glucocorticoid deficiency have loss-of-function
missense mutations in MC2R and 20% have
mutations in MRAP, which encodes melanocortin 2 receptor accessory protein—a small,
single-transmembrane-domain protein that is
required for MC2-R expression at the cell surface.
Familial glucocorticoid deficiency is potentially
lethal. Affected individuals are subject to hypoglycemia and infection, in infancy or childhood.
Typically, they have low levels of glucocorticoids
and extremely high levels of ACTH and
α-melanocyte-stimulating hormone, which
results in skin hyperpigmentation.25,26
No gain-of-function mutations of MC2-R
have been found in cortisol-secreting tumors. In
these tumors the cAMP pathway, which is physiologically stimulated by ACTH, is frequently
activated by aberrant GPCRs. In particular,
abnormal expression of the receptor for gastric
inhibitory polypeptide causes ‘food-dependent’
Cushing’s syndrome, in which cortisol levels
increase after meals in response to the physiological postprandial rise of gastric inhibitory
polypeptide.27 Other GPCRs that are aberrantly expressed in cortisol-secreting adenomas
and associated with Cushing’s syndrome are the
LHR and β-adrenergic receptors.28
GPCR MUTATIONS AND OBESITY
Loss-of-function mutations in melanocortin 4
receptor (MC4-R)—which, together with
melanocortin receptor 3, is the predominant
anorexigenic receptor involved in hypothalamic
control of food intake—is the most common
monogenic disorder in obesity, accounting for
1–6% of cases of early-onset or severe adult
obesity.29,30 Loss of MC4-R function is generally
caused by heterozygous missense mutations,
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which segregate with obesity and show incomplete
penetrance. There is a good correlation between
the severity of defective MC4-R function in vitro
and the amount of food ingested at a test meal.31
Affected individuals exhibit hyperphagia that
often starts in the first year of life, severe obesity,
increased bone mineral density, increased linear
growth, and severe hyperinsulinemia.30
GPCR MUTATIONS AND GROWTH
DISORDERS
Growth-hormone releasing hormone receptor
Homozygous, loss-of-function mutations of
the growth hormone (GH)-releasing-hormone
receptor gene (GHRHR) are a rare cause of familial,
isolated, GH deficiency.32,33 Affected patients
show early and severe growth failure during the
first year of life, with low GH and insulin-like
growth factor 1 levels that are unresponsive to
GH-releasing hormone. They have particular
phenotypic characteristics—a high-pitched voice,
mild frontal bossing, and abdominal adiposity.
No gain-of-function mutations in GHRHR have
been described.34
Ghrelin and GH secretagogue receptor
In 2006, a missense mutation within the first
exon of GHSR (the gene that encodes GHS-R,
the receptor for ghrelin and GH secretagogues),
was identified in two unrelated families. This
mutation is a substitution that has been found
in homozygous and heterozygous forms, and
has a dominant mode of inheritance and incomplete penetrance. The mutation segregates
with short stature and results in decreased cellsurface expression of GHS-R, which selectively
impairs the constitutive activity of GHS-R while
preserving its ability to respond to ghrelin.35
GPCR MUTATIONS AND WATER BALANCE
Loss-of-function mutations in the vasopressin V2
receptor (AVPR V2) are present in approximately
90% of patients with nephrogenic diabetes insipidus (NDI), a rare disorder due to renal distal
nephron insensitivity to the action of antidiuretic
hormone (ADH, also known as arginine vasopressin).36,37 NDI is an X-linked recessive disease
and affected patients are male, although female
patients with NDI and heterozygous mutations in
the AVPR2 gene have been reported, in whom the
condition is probably caused by skewed X inactivation.38,39 The remaining 10% of patients have
autosomal NDI, due to mutations in AQP2, the
aquaporin-2 renal collecting duct water channel
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gene.37 To date, more than 200 distinct AVPRV2
mutations, which are associated with nonspecific
symptoms in the first year of life (e.g. anorexia,
vomiting, fever, growth and development retardation, and excretion of large volumes of hypotonic urine) and frequently complicated by
severe dehydration in adult life, have been identified.37 These mutations are scattered throughout
the AVPR V2 protein, with the exception of the
C-terminal and N-terminal tails.40
In 2005, hemizygous gain-of-function AVPR2
mutations were identified in two unrelated
male infants with signs and symptoms consistent with the syndrome of inappropriate ADH
secretion (SIADH), a condition characterized
by inappropriately concentrated urine, hyponatremia, hypo-osmolality and natriuresis.41
In contrast to classical SIADH, this particular
subtype of the condition (termed ‘nephrogenic
syndrome of inappropriate antidiuresis’) is
characterized by low ADH levels, consistent with
the presence of activating AVPR V2 mutations.41
Taking into account that 10–20% of patients
with SIADH have low ADH levels, it is tempting
to speculate that the nephrogenic syndrome of
inappropriate antidiuresis might not be so rare.
GPCR MUTATIONS AND MINERAL ION
TURNOVER
Calcium-sensing receptor
The calcium-sensing receptor (CaSR) allows
parathyroid and kidney tubular cells to sense the
extracellular calcium concentrations and to
regulate parathyroid hormone (PTH) secretion
and tubular calcium reabsorption, accordingly.
By this mechanism, elevated calcium concentrations inhibit PTH secretion and calcium
reabsorption in the kidney thick ascending limb
and, therefore, increase urinary calcium excretion. Both loss-of-function and gain-of-function
mutations of the CaSR have been identified.42–44
Homozygous loss-of-function missense or
nonsense mutations, scattered throughout most
of the CaSR, cause neonatal severe primary
hyperparathyroidism,42,43 a rare disease that
requires early diagnosis and parathyroidectomy
to permit affected individuals to survive. The
loss of a functional CaSR means that neither
PTH secretion nor calcium reabsorption is
inhibited even in the presence of high calcium
concentrations, which results in hypercalcemia,
hypercalciuria and parathyroid tumors. In
heterozygous individuals these mutations cause
familial hypocalciuric hypercalcemia, a rare,
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autosomal-dominant disorder characterized by
hypercalcemia, inappropriately low urinary
calcium excretion and (usually) normal PTH
levels. This disorder is considered to be benign
and is, therefore, often termed familial
benign hypocalciuric hyercalcemia, although
affected individuals probably have an increased
incidence of chondrocalcinosis, pancreatitis
and osteomalacia.43
Gain-of-function mutations of CaSR are associated with familial hypercalciuric hypocalcemia
syndrome. These mutations are located within
the extracellular domain of the protein, and
lead to suppression of PTH secretion and to
inappropriately increased calcium excretion in the
presence of low serum calcium concentrations.43–47
This condition needs to be distinguished from
hypoparathyroidism, since patients with CaSR
mutations can experience increased hypercalciuria,
nephrocalcinosis and renal impairment if treated
with calcium and vitamin D supplementation.48
Parathyroid hormone receptor 1
Loss-of-function and gain-of-function mutations
in the PTH receptor 1 gene cause two disorders
characterized by abnormalities in endochondral
bone formation. Loss-of-function mutations
in PTH receptor 1 cause Blomstrand chondrodysplasia, a recessive disorder characterized by
accelerated skeletal maturation, inappropriate
cartilage ossification, craniofacial malformations, coarctation of the aorta, and fetal death.49
Heterozygous gain-of-function mutations are
responsible for Jansen-type metaphyseal chondrodysplasia. This disease is a rare form of shortlimbed dwarfism that is usually associated with
normal or suppressed levels of serum PTH and
severe hypercalcemia and hypophosphatemia,
which mimics primary hyperparathyroidism.50
of the reaction is determined by GTP hydrolysis.
The α-subunit-triggered effectors are enzymes of
second-messenger metabolism, such as cAMPdependent and phosphatidylinositol kinases,
and ion channels. They induce short-term effects
on hormone secretion, neurotransmission and
muscle contraction as well as long-term effects
on gene transcription52 (Figure 1). The seventeen α subunits that have been cloned so far are
divided into major subfamilies, according to the
nature of the generated second messenger.
G-PROTEIN MUTATIONS AND DISEASE
To date, only guanine nucleotide-binding protein
G-stimulating subunit α (Gsα) and guanine
nucleotide-binding protein G-transducing
activity α1 subunit (Gtα, also known as the transducin α1 chain) have been unequivocally associated with human diseases. Indeed, data that
reported somatic gain-of-function mutations of
Gi2α protein (which is involved in the inhibition
of adenylyl cyclase and activation of mitogenic
pathways) in subsets of ovarian sex cord
stromal tumors, adrenal cortex tumors and pituitary nonfunctioning tumors have not been
subsequently confirmed.51 Loss-of-function
mutations of the Gtα gene (GNAT1) cause
autosomal-dominant stationary night blindness
(Nougaret syndrome).53 Loss-of-function or
gain-of-function mutations in the gene that
encodes Gsα (GNAS, formerly known as GNAS1)
cause endocrine disorders characterized by
hormone resistance or hormone excess, respectively.54 Germline, loss-of-function mutations
are always heterozygous, and gain-of-function
mutations are always somatic, presumably
because complete loss or constitutive activation
of GNAS in the germline is lethal.54
Loss-of-function mutations of GNAS
G PROTEINS
G proteins are molecular switches whose activities are determined by their interaction with
guanine nucleotides, hence their name (Figure 1).
They are composed of three subunits—α, β and
γ. The functional specificity of each G protein
depends on the α subunit, which differs from
one G protein to another.51 The GDP-bound
α subunit binds tightly to the β–γ complex and
is inactive, whereas the GTP-bound α subunit
can dissociate from the β–γ complex and activate
effector proteins. The interaction of an agonist
with a specific GPCR causes the exchange of GDP
for GTP in the α subunit, whereas the duration
DECEMBER 2006 VOL 2 NO 12 LANIA ET AL.
Heterozygous, loss-of-function mutations of
GNAS cause Albright’s hereditary osteodystrophy
(AHO), a syndrome characterized by several
physical features, including short stature, obesity,
subcutaneous ossifications, brachydactyly and
mental deficiency.54–56 Consistent with the presence of heterozygous mutations, haploinsufficiency is probably responsible for these
multiple defects. In addition to the AHO phenotype, patients who inherit the mutation from
their mother develop resistance to the actions
of PTH, which is frequently associated with
resistance to other hormones that act via
Gsα-coupled receptors, such as TSH, GHRH and
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gonadotropins. This rare condition is referred
to as pseudohypoparathyroidism type 1a
(PHP1a).54,56 Female patients develop resistance
to PTH, TSH, GHRH and gonadotropins, of
variable severity and time course.56–58 Patients
who inherit the same GNAS mutations from
their father have AHO without any resistance
to hormone action, a condition defined as
pseudopseudohypoparathyroidism (PPHP).
The differences between the PHP1a and
PPHP phenotypes are caused by genomic
GNAS imprinting (imprinting is an epigenetic
event that causes expression of one allele,
either maternal or paternal, to be suppressed).
Indeed, Gsα is biallelically expressed in most
tissues, whereas it is primarily expressed from
the maternal allele in others, particularly renal
proximal tubules, thyroid, gonads and pituitary.57,59,60 In these tissues, mutations in the
active, maternal allele lead to Gsα deficiency and
hormone resistance (i.e. PHP1a) whereas mutations in the inactive, paternal allele have little
or no effect (i.e. PPHP); moreover, silencing of
one allele can be total or partial, and may occur
either during embryogenesis or in postnatal life,
which is consistent with the observed variation
in the PHP1a phenotype.
Some patients with AHO develop a severe form
of ectopic ossification referred to as progressive osseous heteroplasia, in which connective
tissues and muscles are invaded by large, ossified plaques. Since the mutations in patients with
AHO or progressive osseous heteroplasia are
similar, other genetic or environmental factors
are presumed to be involved in this process.61
An intriguing missense mutation of GNAS
has been identified in two unrelated males who
presented with AHO, PTH resistance and testotoxicosis. This substitution (Ala366Ser) causes
a rapid GDP release from Gsα, and results in
activation of cAMP production at the reduced
temperature of the testis and in LH-independent
stimulation of Leydig cells; however, the mutant
protein is thermolabile at 37 °C, which results in
the AHO phenotype.62
Resistance to PTH in the absence of AHO
and other endocrine abnormalities is referred
to as PHP1b, a usually sporadic but occasionally familial defect with an autosomal-dominant
pattern of transmission. Linkage analysis has
mapped the genetic locus to a small region of
chromosome 20q13.3, where GNAS is located. The
proposed mechanism of disease is the presence
of specific deletions, which differ in familial
688 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM
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and sporadic PHP1b and disrupt long-range
imprinting of the control elements of this locus,
with consequent decreased GNAS transcription
in renal proximal tubules.63–66
Gain-of-function mutations of GNAS
Activating GNAS mutations were first identified in GH-secreting pituitary adenomas.67
The only substitutions so far described occur at
either Arg201 or Gln227 and cause constitutive
activation of cAMP formation, by inhibition of
the intrinsic GTPase activity of the G-protein
α subunit. Since pituitary somatotrophs belong
to a cell type that recognizes cAMP as a mitogen,
GNAS can be considered to be a proto-oncogene
that is converted into an oncogene, designated
GSP (Gs protein), in selected cell types.
Following the identification of GSP mutations
in about 30–40% of GH-secreting adenomas,
analogous mutations have been detected
in a small subset of other pituitary tumors, in
5–10% of toxic thyroid adenomas and thyroid
cancers, in some cortisol-secreting adenomas
and in a significant proportion of ovarian and
testicular stromal Leydig cell tumors.68 In the
past 3 years, these same mutations have been
described in girls with premature thelarche, and
in juvenile ovarian granulosa cell tumors.69,70
With the exception of juvenile ovarian granulosa
cell tumors, neoplastic lesions associated with the
GSP oncogene are benign, well-differentiated,
hormone-hypersecreting adenomas, without
significant clinical and biochemical differences
from lesions that express wild-type Gsα protein;71
this phenomenon is probably caused by the activation of counter-regulatory mechanisms.72,73A
variety of Gsα mutations at Arg201 lead to
McCune–Albright syndrome (MAS), a rare
disorder characterized by polyostotic fibrous
dysplasia, café-au-lait skin hyperpigmentation,
and autonomous hyperfunction of several
endocrine glands.74 These tissue-specific effects
are caused by mosaicism for the Gsα mutation,
consistent with a somatic GNAS mutation that
occurs as an early postzygotic event. Interestingly,
in patients with MAS who have acromegaly,
as well as in isolated GH-secreting adenomas,
these GNAS mutations are in the maternal allele,
presumably because in somatotroph cells Gsα is
almost exclusively expressed from this allele.75
Finally, substitutions at Arg201 are also found in
isolated fibrous dysplasia and in intramuscular
myxomas, which occur outside of the context of
typical MAS.76
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Table 3 Clinical and biochemical features of ‘nonsyndromic’ diseases, which might be caused by GPCR mutations that lead to
endocrine disorders.
Clinical features
Biochemical feature
Possible GPCR affected
(type of mutation)
Normal or low TSH, low FT4, absent TSH
and prolactin responses to TRH test
Moderately high TSH, normal FT4, no goiter,
no antibodies to thyroglobulin or thyroperoxidase
High TSH, low FT4, no goiter, no antibodies
to thyroglobulin or thyroperoxidase
TRH receptor (inactivating)
Low TSH, high FT4, no antibodies to
thyroglobulin, or TSH receptor
Low TSH, high FT4
TSH receptor (activating)
Low sex steroids and low-normal LH and FSH,
responsive to GnRH test
Low sex steroids and low-normal LH and FSH,
poorly responsive to GnRH test
Kisspeptin 1 receptor (inactivating)
Androgenic insufficiency with ‘normal’
spermatogenesis, eunuchoidal features
Low LH and testosterone levels, normal FSH
GnRH receptor (inactivating)
Complete male pseudohermaphroditism, to very
mild undervirilization with hypoplasia and/or
agenesis of Sertoli cells
High LH, normal FSH, barely detectable
testosterone, unresponsive to hCG
LH receptor (inactivating)
Primary amenorrhea with normal development of
primary and secondary sexual characteristics
High LH, normal or high FSH, and low estradiol
and progesterone, unresponsive to hCG
LH receptor (inactivating)
Male precocious puberty with normal pituitary MRI
High testosterone and low LH and FSH with
prepubertal response to GnRH test
LH receptor (activating)
Primary or early-onset secondary amenorrhea,
variable development of secondary sex characteristics
and premature arrest of follicular maturation
High LH, high FSH
FSH receptor (inactivating)
Ovarian hyperstimulation syndrome during in vitro
fertilizationa
None
FSH receptor (activating)
Low cortisol, high ACTH, no response to ACTH
stimulation test, normal renin–angiotensin system
Melanocortin 2 receptor
(inactivating)
Thyroid disorders
Isolated central hypothyroidism with normal
pituitary MRI
Partial hypothyroidism
Complete congenital hypothyroidism
Juvenile hyperthyroidism with goiter
Gestational hyperthyroidism with spontaneous
remission after delivery
TRH receptor (inactivating)
TRH receptor (inactivating)
Gonadal disorders
Delayed puberty
GnRH receptor (inactivating)
Adrenal disorders
Isolated central hypoadrenalism
aSymptoms
range from discomfort to potentially life-threatening, massive ovarian enlargement and capillary leak with fluid sequestration. Abbreviations: ACTH,
adrenocorticotropic hormone; FSH, follicle-stimulating hormone; FT4, free T4; GnRH, gonadotropin-releasing hormone; GPCR, G-protein-coupled receptor;
hCG, human chorionic gonadotropin; LH, luteinizing hormone; TRH, TSH-releasing hormone.
Polymorphic variants of GPCRs
and G proteins
The association of polymorphic variants of
GPCRs and G proteins with disorders of multifactorial etiology has been widely investigated.
In this respect, susceptibility to obesity and
type 2 diabetes has been found to be associated
with polymorphisms of DRD2 (which encodes
the dopamine D2 receptor) and HTR2C, which
encodes the 5-hydroxytryptamine (serotonin) 2C
receptor. Susceptibility to type 1 diabetes seems
to be associated with CC chemokine receptor 2
variants. Previous studies also reported an
increased risk of hypertension associated with
DECEMBER 2006 VOL 2 NO 12 LANIA ET AL.
genetic variants of β2 adrenergic and angiotensin II type 1 receptors.77 On the basis of the
notion that genetic polymorphisms could influence a patient’s response to drugs, GPCRs have
been investigated in pharmacogenetic studies.
In this respect, two known polymorphisms in
FSHR seem to be of clinical relevance, since they
are associated with an altered ovarian response to
pharmacologic doses of FSH and should, therefore, be considered in women who are undergoing
controlled ovarian hyperstimulation.78
As for G proteins, studies have reported associations between polymorphic variants of GNAS
and hypertension, alcohol consumption, and
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Table 4 Clinical and biochemical features of ‘nonsyndromic’ endocrine diseases, which might be caused
by GPCR mutations that lead to disorders in weight, growth, water balance and mineral-ion turnover.
Clinical features
Biochemical feature
Possible GPCR
affected (type of
mutation)
Hyperinsulinemia
Melanocortin 4
receptor (inactivating)
Low GH and insulin-like growth factor 1,
unresponsive to GHRH test
GHRH receptor
(inactivating)
Nephrogenic diabetes insipidus
Hypernatremia, low urine osmolality, normal
or high ADH, no response of urinary cyclic
AMP to vasopressin
AVPR V2 (inactivating)
Nephrogenic syndrome of
inappropriate antidiuresis
Hyponatremia, low serum osmolality,
inappropriately high urine osmolality,
undetectable ADH levels
AVPR V2 (activating)
Severe neonatal hyperparathyroidism
High PTH, hypercalcemia,
hypophosphatemia, hypercalciuria
CaSR (inactivating,
homozygous)
Familial hypocalciuric hypercalcemia
Normal PTH, hypercalcemia,
hypermagnesemia, hypocalciuria
CaSR (inactivating,
heterozygous)
Familial hypercalciuric hypocalcemia
Low PTH, hypocalcemia,
hyperphosphatemia, hypomagnesemia,
hypercalciuria
CaSR (activating)
Obesity
Early-onset or severe adult obesity,
associated with hyperphagia,
increased linear growth, increased
bone mass
Growth disorders
Dwarfism associated with highpitched voice, mild frontal bossing
and abdominal adiposity
Water balance disorders
Mineral-ion turnover disorders
Abbreviations: ADH, antidiuretic hormone; AVPR V2, arginine vasopressin receptor 2; CaSR, calcium-sensing receptor;
GH, growth hormone; GHRH, GH-releasing hormone; GPCR, G-protein-coupled receptor; PTH, parathyroid hormone.
cigarette smoking,79,80 whereas the 825C>T
poly morphism in GNB3, which encodes
guanine nucleotide-binding protein subunit β3
(transducin beta chain 3) has been associated
with hypertension, atherosclerosis, and type 2
diabetes.80,81
More clinical studies are warranted to confirm
these associations, and to investigate the possible usefulness of genotyping for GPCR and
G-protein variants.
CONCLUSIONS
GPCRs and G proteins are molecules that are
required for the transmission of a wide series of
endogenous and exogenous signals. The broad
range of physiologic functions that are associated
with GPCRs explains why at least half of the
currently available medications target this receptor
family. Naturally occurring loss-of-function or
gain-of-function mutations in genes that encode
GPCRs and G proteins are associated with
human endocrine-related diseases, which mimic
690 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM
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hormone deficiency or excess, respectively. The
study of the phenotypic consequences of these
mutations, in naturally occurring cases as well as
in knockout and transgenic mouse models, has
already had major implications for understanding
structure–function relationships in GPCRs and
G proteins, as well as tissue expression specificity,
and function redundancy of these molecules.
The diseases caused by these genetic defects
are rare, and diagnosis requires careful clinical
and biochemical work-up, great awareness of
the potential variation in phenotypes, and close
collaboration between clinical and molecular
endocrinologists. A schematic summary that
outlines the appropriate diagnostic tests that can
lead clinicians to suspect the various mutations
described in this article is given in Tables 3 and 4.
There are significant numbers of patients in
whom no mutations of candidate genes have
been found, which suggests that further research
into potentially disease-causing mutations,
informed by careful analysis of their relevant
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phenotypes, is likely to be fruitful. Moreover,
polymorphic variants that result in subtle functional differences might contribute to multifactorial disease susceptibility. Unfortunately,
once GPCR and G-protein mutations are identified in a patient, the implications for their treatment are, as yet, rather limited. It is predictable,
however, that novel approaches to treatment—
such as the development of inverse agonists
that can block constitutively activated GPCRs,
or methods to rescue the function of inactive
GPCRs—will be available in the future.
6
7
8
9
10
11
KEY POINTS
■
Genes that encode G-protein-coupled
receptors (GPCRs) and G proteins can have
loss-of-function or gain-of-function mutations,
which result in endocrine disorders
■
Loss-of-function mutations in GPCRs and
G proteins prevent signaling in response to the
corresponding agonist, and cause
resistance to hormone action, which mimics
hormone deficiency
■
■
Gain-of-function mutations in GPCRs and
G proteins lead to constitutive, agonistindependent activation of signaling, which
mimics hormone excess
The diseases caused by genetic defects in
GPCRs and G proteins are rare, and diagnosis
requires careful clinical and biochemical
work-up as well as close collaboration between
clinical and molecular endocrinologists
12
13
14
15
16
17
18
■
The study of the phenotypic consequences
of mutations in GPCRs and G proteins
has already had major implications for
understanding structure–function relationships
of these molecules, even if the implications
for treatment of patients who carry such
mutations are limited, at present
19
20
21
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Acknowledgments
This work was supported by
Associazione Italiana per la
Ricerca sul Cancro (AIRC),
Milan, and Ricerca Corrente
Funds of Fondazione
Policlinico Istituti di
Ricovero e Cura a Carattere
Scientifico (IRCCS), Milan,
Italy.
Competing interests
The authors declared
they have no competing
interests.
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