GNAS1 mutational analysis in pseudohypoparathyroidism

Ahmed, S. Faisal; Dixon, Peter H.; Bonthron, David T.; Stirling, Heather; Barr, D. G. D.; Kelnar, C. J. H.; Thakker, Rajesh

doi:10.1046/j.1365-2265.1997.1100922.x-i1

Cited by 75 publications

(31 citation statements)

References 28 publications

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“…members affected with either PHP Ia or PPHP. On the contrary, no mutation in the GNAS1 coding sequence has ever been found in families in whom sporadic or familial PPHP was the only clinical manifestation (48,63,64). These results support the view that PHP Ia and isolated PPHP may represent two genetically distinct entities, even if the possibility that a defect may exist in the promoter region or in other regulatory intronic sequences of GNAS1 cannot be completely excluded.…”

Section: Albright Hereditary Osteodystrophy and Pseudohypoparathyroidismsupporting

confidence: 73%

G protein mutations in endocrine diseases

Lania

Mantovani

Spada

2001

European Journal of Endocrinology

100

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This review summarizes the pathogenetic role of naturally occurring mutations of G protein genes in endocrine diseases. Although in vitro mutagenesis and transfection assays indicate that several G proteins have mitogenic potential, to date only two G proteins have been identi®ed which harbor naturally occurring mutations, Gsa, the activator of adenylyl cyclase and Gi2a, which is involved in several functions, including adenylyl cyclase inhibition and ion channel modulation. The gene encoding Gsa (GNAS1) may be altered by loss or gain of function mutations. Indeed, heterozygous inactivating germ line mutations in this gene cause pseudohypoparathyroidism type Ia, in which physical features of Albright hereditary osteodystrophy (AHO) are associated with resistance to several hormones, i.e. PTH, TSH and gonadotropins, that activate Gs-coupled receptors or pseudopseudohypoparathyroidism in which AHO is the only clinical manifestation. Evidence suggests that the variable and tissue-speci®c hormone resistance observed in PHP Ia may result from tissuespeci®c imprinting of the GNAS1 gene, although the Gsa knockout model only in part reproduces the human AHO phenotype. Activating somatic Gsa mutations leading to cell proliferation have been identi®ed in endocrine tumors constituted by cells in which cAMP is a mitogenic signal, i.e. GH-secreting pituitary adenomas, hyperfunctioning thyroid adenomas and Leydig cell tumors. When the same mutations occur very early in embryogenesis they cause McCune±Albright syndrome. Although these mutations would in principle confer growth advantage, studies failed to detect differences in the clinical and hormonal phenotypes, suggesting the existence of mechanisms able to counteract the activation of the cAMP pathway. Activating mutations of Gi2a have been identi®ed in a subset of ovarian, adrenal and pituitary tumors, but their prevalence and signi®cance are still controversial. Finally, although Ga subunits are the only components of the heterotrimeric GTP binding proteins which harbor known mutations, b/g subunits should be considered possible targets of genetic alterations as suggested by the frequent presence of b3 subunit variants in patients with essential hypertension.

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Section: Albright Hereditary Osteodystrophy and Pseudohypoparathyroidismsupporting

confidence: 73%

G protein mutations in endocrine diseases

Lania

Mantovani

Spada

2001

European Journal of Endocrinology

100

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“…An amino acid substitution at codon 115 has been described by Ahmed et al (34): their mutation is different from ours because the proline is replaced by a serine, instead of a leucine. Both nuclear magnetic resonance and crystal structure studies of G s␣ demonstrate that proline 115 is important for correct protein folding (34,35). Its substitution is predicted to disrupt the highly conserved domain of G s␣ that interacts with adenylate cyclase (36).…”

Section: Discussionmentioning

confidence: 99%

Molecular Analysis of the GNAS1 Gene for the Correct Diagnosis of Albright Hereditary Osteodystrophy and Pseudohypoparathyroidism

et al. 2003

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Pseudohypoparathyroidism (PHP) is a heterogeneous disease characterized by PTH resistance and classified as types Ia, Ib, Ic, and II, according to its different pathogenesis and phenotype. PHP-Ia patients show G s␣ protein deficiency, PTH resistance, and typical Albright hereditary osteodystrophy (AHO). Heterozygous mutations in the GNAS1 gene encoding the G s␣ protein have been identified both in PHP-Ia and in pseudopseudohypoparathyroidism (PPHP), a disorder with isolated AHO. A single GNAS1 mutation may be responsible for both PHP-Ia and PPHP in the same family when inherited from the maternal and the paternal allele, respectively, suggesting that GNAS1 is an imprinted gene. To evaluate whether molecular diagnosis is a useful tool to characterize AHO and PHP when testing for G s␣ activity and PTH resistance is not available, we have performed GNAS1 mutational analysis in 43 patients with PTH resistance and/or AHO. Sequencing of the whole coding region of the GNAS1 gene identified 11 mutations in 18 PHP patients, eight of which have not been reported previously. Inheritance was ascertained in 13 cases, all of whom had PHP-Ia: the mutated alleles were inherited from the mothers, who had AHO (PPHP), consistent with the proposed imprinting mechanism. GNAS1 molecular analysis confirmed the diagnosis of PHP-Ia and PPHP in the mutated patients. Our results stress the usefulness of this approach to obtain a complete diagnosis, expand the GNAS1 mutation spectrum, and illustrate the wide mutation heterogeneity of PHP and PHP-Ia. PHP (OMIM 103580) was the first human disease to be ascribed to deficient responsiveness to a hormone by otherwise normal target organs (1). It consists of a heterogeneous group of endocrine disorders, whose common feature is resistance to PTH, as shown by hypocalcemia, hyperphosphatemia, and elevation of serum PTH despite normal renal function (2). PTH stimulates the formation of intracellular cAMP by adenylyl cyclase through the activation of G s protein (3, 4). G s protein belongs to the superfamily of heterotrimeric G proteins formed of three subunits (␣, ␤, ␥) encoded by separate genes (5). They mediate signal transduction across cell membranes by coupling extracellular receptors to intracellular effector proteins. The activity of hormone-sensitive adenylate cyclase is regulated by at least two G proteins, one stimulatory (G s ) and one inhibitory (G i ). G protein specificity is defined by its specific ␣-subunit. G s␣ , which binds GTP and stimulates adenylyl cyclase, has GTPase activity and couples multiple receptors to the stimulation of adenylyl cyclase, including those for PTH, TSH, and LH/FSH.

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“…The R231H mutation was reported previously . Data for mutations were derived from the following references (Ahmed et al 1998;Farfel et al 1996;Fischer et al 1998;Iiri et al 1994;Miric et al 1993;Oude-Luttikhuis et al 1994;Pattern et al 1990;Schwindinger et al 1994;Shapira et al 1996;Warner et al 1997Warner et al , 1998Weinstein et al 1990Weinstein et al , 1992Yu et al 1995Yu et al , 1999 NA, Not available; PTH, parathyroid hormone; TRH, thyroidstimulating hormone (TSH) releasing hormone; T4, thyroxine; T3, triiodothyronine a PTH infusion test was performed using bolus synthetic PTH-(1-34), at 100 U/m 2 . Basal levels are the mean urinary cyclic (c)AMP (nmol/h) and urinary phosphate-to-creatine ratio for two urine samples taken in the 2 h before the administration of PTH.…”

Section: Patientmentioning

confidence: 99%

“…1) (Ahmed et al 1998;Farfel et al 1996;Fischer et al 1998;Iiri et al 1994;Miric et al 1993;OudeLuttikhuis et al 1994;Pattern et al 1990;Schwindinger et al 1994;Shapira et al 1996;Warner et al 1997Warner et al , 1998Weinstein et al 1990Weinstein et al , 1992Yu et al 1995Yu et al , 1999. The widespread deficiency of Gs protein can explain the resistance to PTH and other hormones whose receptors are coupled to Gs; however, the relationship between AHO phenotypes and Gsα mutations remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Two mutations of the Gsα gene in two Japanese patients with sporadic pseudohypoparathyroidism type Ia

et al. 2001

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Pseudohypoparathyroidism Ia (PHP-Ia), is an inherited disease with clinical hypoparathyroidism caused by parathyroid hormone resistance (PTH), and shows the phenotype of Albright hereditary osteodystrophy (AHO), including short stature, obesity, round face, brachydactyly, and subcutaneous ossification. This disease is caused by mutation that inactivates the α-subunit of Gs, the stimulatory regulator of adenylyl cyclase. Here, a novel frameshift mutation (delG at codon 88) in exon 4, and a missense mutation (R231H) in exon 9 of the Gsα gene were identified in two Japanese patients with sporadic PHP-Ia. Deletion of a G in exon 4 at codon 88 in the first patient produced a premature stop codon, resulting in the truncated protein. The second patient had a previously reported R231H mutation. Because this amino acid is located in a region, switch 2, that is thought to interact with the γ subunit of Gsα protein, this mutation may impair Gs protein function. We report here one novel Gsα mutation, and note that mutations in Japanese patients with PHP-Ia are probably heterogeneous.

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GNAS1 mutational analysis in pseudohypoparathyroidism

Cited by 75 publications

References 28 publications

G protein mutations in endocrine diseases

G protein mutations in endocrine diseases

Molecular Analysis of the GNAS1 Gene for the Correct Diagnosis of Albright Hereditary Osteodystrophy and Pseudohypoparathyroidism

Two mutations of the Gsα gene in two Japanese patients with sporadic pseudohypoparathyroidism type Ia

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