Mutations of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis.

Weinstein, Lee S.; Gejman, Pablo V.; Friedman, Eitan; Kadowaki, Takashi; Collins, Regina; Gershon, Elliot S.; Spiegel, Allen M.

doi:10.1073/pnas.87.21.8287

Cited by 243 publications

(133 citation statements)

References 30 publications

(23 reference statements)

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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%

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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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Section: Patientmentioning

confidence: 99%

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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“…Patients with PHP Ia show a distinct physical phenotype characterized by short stature, obesity, brachydactyly, subcutaneous calcifications and mental retardation known as Albright's hereditary osteodystrophy (AHO) (1). The underlying cause for the reduced activity of the Gsa protein is the inactivation of the protein due to heterozygous mutations within the coding GNAS gene (3). The human GNAS gene is located on chromosome 20q13, with a coding region consisting of 13 exons (4).…”

Section: Introductionmentioning

confidence: 99%

Early manifestation of calcinosis cutis in pseudohypoparathyroidism type Ia associated with a novel mutation in the GNAS gene

et al. 2005

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Objective: To clarify the molecular defect for the clinical finding of congenital hypothyroidism combined with the manifestation of calcinosis cutis in infancy. Case report: The male patient presented with moderately elevated blood thyrotropin levels at neonatal screening combined with slightly decreased plasma thyroxine and tri-iodothyronine concentrations, necessitating thyroid hormone substitution 2 weeks after birth. At the age of 7 months calcinosis cutis was seen and the patient underwent further investigation. Typical features of Albright's hereditary osteodystrophy (AHO), including round face, obesity and delayed psychomotor development, were found. Methods and results: Laboratory investigation revealed a resistance to parathyroid hormone (PTH) with highly elevated PTH levels and a reduction in adenylyl cyclase-stimulating protein (Gsa) activity leading to the diagnosis of pseudohypoparathyroidism type Ia (PHP Ia). A novel heterozygous mutation (c364T . G in exon 5, leading to the amino acid substitution Ile-106 ! Ser) was detected in the GNAS gene of the patient. This mutation was not found in the patient's parents, both of whom showed normal Gsa protein activity in erythrocytes and no features of AHO. A de novo mutation is therefore likely. Conclusions: Subcutaneous calcifications in infancy should prompt the clinician to a thorough search for an underlying disease. The possibility of AHO and PHP Ia should be considered in children with hypothyroidism and calcinosis cutis. Systematic reviews regarding the frequency of calcinosis in AHO are warranted.

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“…A defect in this protein is reported in patients with pseudohypoparathyroidism (PHP), which is characterized by reduced expression or function of the a subunit of the stimulatory G-protein (Gsa) in the action of parathyroid and other hormones that use cyclic AMP as an intracellular second messenger. A defect in the G-protein could cause multiple hormone resistance in patients with PHP [23][24][25][26][27][28]. Because of the hormonal data and cAMP response in our patients, it seems that they do not have a defect in the G-proteins.…”

Section: Discussionmentioning

confidence: 63%

Siblings with ACTH Insensitivity Due to Lack of ACTH Binding to the Receptor.

et al. 1995

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Abstract. We report two siblings, a 9-year-old boy and 4-year-old girl, with ACTH insensitivity. They were referred to our hospital because of pigmentation of the skin. They had normal plasma cortisol and urinary 17-OHCS levels despite markedly high plasma ACTH, and these did not respond to consecutive 3-day ACTH-Z administration, but plasma aldosterone responded normally to increased plasma renin activity after a low sodium diet. We examined the characteristics of ACTH receptors in peripheral blood mononuclear leukocytes (MNLs) obtained from the patients and their family. Adenylate cyclase generation caused by an addition of ACTH did not occur in MNLs from the patients.In studies on ACTH binding to MNLs, a lack of high-affinity ACTH binding was observed in the patients. These results suggest that the patients have a defect in ACTH binding to the receptors, resulting in ACTH insensitivity. The reason for this defect in ACTH binding remains unclear because no significant mutation in the ACTH receptor DNA sequence was detected in the MNLs of these patients.

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Mutations of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis.

Cited by 243 publications

References 30 publications

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

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

Early manifestation of calcinosis cutis in pseudohypoparathyroidism type Ia associated with a novel mutation in the GNAS gene

Siblings with ACTH Insensitivity Due to Lack of ACTH Binding to the Receptor.

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