Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Albright hereditary osteodystrophy (AHO), an autosomal dominant disorder characterized by short stature, obesity, and skeletal defects, is associated with heterozygous inactivating mutations of GNAS1, the gene encoding the heterotrimeric G protein alpha-subunit (Gsalpha) that couples multiple receptors to the stimulation of adenylyl cyclase. It has remained unclear why only some AHO patients present with multihormone resistance and why AHO patients demonstrate resistance to some hormones [e.g., parathyroid hormone (PTH)] but not to others (e.g., vasopressin), even though all activate adenylyl cyclase. We generated mice with a null allele of the mouse homolog Gnas. Homozygous Gs deficiency is embryonically lethal. Heterozygotes with maternal (m-/+) and paternal (+/p-) inheritance of the Gnas null allele have distinct phenotypes, suggesting that Gnas is an imprinted gene. PTH resistance is present in m-/+, but not +/p-, mice. Gsalpha expression in the renal cortex (the site of PTH action) is markedly reduced in m-/+ but not in +/p- mice, demonstrating that the Gnas paternal allele is imprinted in this tissue. Gnas is also imprinted in brown and white adipose tissue. The maximal physiological response to vasopressin (urinary concentrating ability) is normal in both m-/+ and +/p- mice and Gnas is not imprinted in the renal inner medulla (the site of vasopressin action). Tissue-specific imprinting of Gnas is likely the mechanism for variable and tissue-specific hormone resistance in these mice and a similar mechanism might explain the variable phenotype in AHO.
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PMID:Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the gsalpha gene. 967 44

Albright hereditary osteodystrophy (AHO), a disorder characterized by skeletal abnormalities and obesity, is associated with heterozygous inactivating mutations in the gene for Gsalpha. A novel Gsalpha mutation encoding the substitution of tryptophan for a nonconserved arginine within the switch 3 region (Gsalpha R258W) was identified in an AHO patient. Although reverse transcription-polymerase chain reaction studies demonstrated that mRNA expression from wild type and mutant alleles was similar, Gsalpha expression in erythrocyte membranes from the affected patient was reduced by 50%. A Gsalpha R258W cDNA, as well as one with arginine replaced by alanine (Gsalpha R258A), was generated, and the biochemical properties of in vitro transcription/translation products were examined. When reconstituted with cyc- membranes, both mutant proteins were able to stimulate adenylyl cyclase normally in the presence of guanosine- 5'-O-(3-thiotriphosphate) (GTPgammaS) but had decreased ability in the presence of isoproterenol or AlF4- (a mixture of 10 microM AlCl3 and 10 mM NaF). The ability of each mutant to bind and be activated by GTPgammaS or AlF4- was assessed by trypsin protection assays. Both mutants were protected normally by GTPgammaS but showed reduced protection in the presence of AlF4-. The addition of excess GDP (2 mM) was able to rescue the ability of AlF4- to protect the mutants, suggesting that they might have reduced affinity for GDP. A Gsalpha R258A mutant purified from Escherichia coli had decreased affinity for GDP and an apparent rate of GDP release that was 10-fold greater than that of wild type Gsalpha. Sucrose density gradient analysis demonstrated that both Gsalpha R258W and Gsalpha R258A were thermolabile at higher temperatures and that denaturation of both mutants was prevented by the presence of 0.1 mM GTPgammaS or 2 mM GDP. The crystal structure of Gsalpha demonstrates that Arg258 interacts with a conserved residue in the helical domain (Gln170). Arg258 substitutions would be predicted to open the cleft between the GTPase and helical domains, allowing for increased GDP release in the inactive state, resulting in enhanced thermolability and reduced AlF4--induced adenylyl cyclase stimulation and trypsin protection, since activation by AlF4- requires bound GDP.
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PMID:A novel mutation in the switch 3 region of Gsalpha in a patient with Albright hereditary osteodystrophy impairs GDP binding and receptor activation. 972 13

Albright hereditary osteodystrophy (AHO) is a genetic disorder characterized by short stature, skeletal defects, and obesity. Within AHO kindreds, some affected family members have only the somatic features of AHO [pseudopseudohypoparathyroidism (PPHP)], whereas others have these features in association with resistance to multiple hormones that stimulate adenylyl cyclase within their target tissues [pseudohypoparathyroidism type Ia (PHP Ia)]. Affected members of most AHO kindreds (both those with PPHP and those with PHP Ia) have a partial deficiency of Gs alpha, the alpha-subunit of the G protein that couples receptors to adenylyl cyclase stimulation, and in a number of cases heterozygous loss of function mutations within the Gs alpha gene (GNAS1) have been identified. Using PCR with the attachment of a high melting domain (GC-clamp) and temperature gradient gel electrophoresis, two novel heterozygous frameshift mutations within GNAS1 were found in two AHO kindreds. In one kindred all affected members (both PHP Ia and PPHP) had a heterozygous 2-bp deletion in exon 8, whereas in the second kindred a heterozygous 2-bp deletion in exon 4 was identified in all affected members examined. In both cases the frameshift encoded a premature termination codon several codons downstream of the deletion. In the latter kindred affected members were previously shown to have decreased levels of GNAS1 messenger ribonucleic acid expression. These results further underscore the genetic heterogeneity of AHO and provides further evidence that PHP Ia and PPHP are two clinical presentations of a common genetic defect. Serial measurements of thyroid function in members of kindred 1 indicate that TSH resistance progresses with age and becomes more evident after the first year of life.
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PMID:Identification of two novel deletion mutations within the Gs alpha gene (GNAS1) in Albright hereditary osteodystrophy. 1048 96

Deficiency of protein Gs (Gs; OMIM no.103580), the stimulatory regulator of adenylyl cyclase, is associated with resistance to PTH and other hormones, sc calcifications, short stature, and skeletal defects (Albright's hereditary osteodystrophy). It is caused by heterozygous loss of function mutations in GNAS 1, the gene encoding the alpha-subunit of Gs. Obesity is a classical feature of patients with Gs deficiency, but the mechanism leading to fat accumulation has not been elucidated. We measured glycerol flux, using a nonradioactive tracer dilution approach, to analyze the lipolytic response to epinephrine in 6 patients with Gs deficiency and PTH resistance and compared it to six age-matched normal controls and nine massively obese children. Basal glycerol production was reduced by 50%, and lipolytic response to epinephrine was reduced by 67%, in Gs-deficient children, as compared with controls. The degree of impairment of lipolysis was similar in Gs-deficient children who were only moderately overweight and in morbidly obese children. These findings extend the spectrum of hormonal resistance in Gs deficiency. Besides beta-adrenergic receptors, Gs protein itself should be examined as a possible step involved in the decreased lipolysis observed in common obesity.
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PMID:Resistance to the lipolytic action of epinephrine: a new feature of protein Gs deficiency. 1056 60

Obesity is a common feature of pseudohypoparathyroidism (PHP) type 1a, but is usually associated with short stature. We describe two children referred because of hyperphagia and excessive weight gain from early infancy. Tall stature in both children initially confounded the diagnosis of PHP, but on follow-up both children developed the typical hormonal abnormalities and Case 2 developed typical skeletal features of Albright hereditary osteodystrophy. PHP type 1a is caused by germline loss of function mutations in the alpha subunit of GS, the ubiquitously expressed G protein that couples many hormone receptors to the adenylate cyclase second messenger system. Recent evidence suggest that the hypothalamic GS protein coupled melanocortin-4 receptor (MC4R) may mediate the central effects of leptin on inhibition of satiety. Similar patterns of infancy onset hyperphagia, excessive weight gain and tall stature are seen in subjects with congenital leptin deficiency and in subjects with MC4R mutations. We suggest that the genetic mutations in GSalpha which underlie PHP type 1a may also directly result in severe obesity. This diagnosis should be considered in any child with a history of hyperphagia and early onset morbid obesity.
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PMID:Pseudohypoparathyroidism--another monogenic obesity syndrome. 1071 39

We presented a case of a 22-year-old woman with pseudohypoparathyroidism type la. She was a typical congenital Albright syndrome patient with osteodystrophy including hands and feet, accompanied by obesity, strabismum, and retardation growth. Her calcium and phosphate levels were within the normal range which was stated during repeated hospitalisation due to infections. The diagnosis of PHPT was made at the age of 22 when the patient suffered twice from tetany seizure accompanied by numbness and tingling sensation in her hands and around the mouth as well as cramps in her legs. Typical phenotype were found: shortness in stature, obesity, rounded face, small hands and shortening of the third, the fourth and the fifth fingers in both hands and the third and the fourth toes in feet together with trophic disorders of nails and valgity of her knees. Somatic sings were accompanied by hypocalcaemia and hyperphosphatemia, hyperphosphatasia, lower calcium and phosphate urinary excretion and three-fold increased PTH serum level. Computerised tomography of the brain showed extensive evidence of cerebral calcification in basal ganglia as well as in dura mater and in skin covering the skull. X-ray and densitometry examinations revealed osteolytic foci in cranial, humeral and forearm bones as well as osteoporosis in palm and feet bones. The patient presented a typical case of PHPT with resistance of the kidney to PTH, what was confirmed by lower calcium and phosphate urinary excretion, with normal bone receptor sensibility to PTH. Elevated PTH levels resulted in osteoporosis and foci of osteolysis. Treatment with calcium and active form of vitamin D3 caused reversal of hypocalcemia symptoms and normalisation of biochemical features. We also found hormonal symptoms of latent hypothyreosis. No coexistence of PTH with thyroid receptor resistance was found. The case was described because it is rare disorder, difficult to diagnose. Early diagnosis and treatment is necessary to limit the irreversible changes as well as bone and central nervous system injury.
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PMID:[A case of pseudohypoparathyroidism]. 1080 May 89

Progressive osseous heteroplasia (POH) is a rare disorder characterized by dermal ossification beginning in infancy followed by increasing and extensive bone formation in deep muscle and fascia. We describe two unrelated girls with typical clinical, radiographic, and histological features of POH who also have findings of another uncommon heritable disorder, Albright hereditary osteodystrophy (AHO). One patient has mild brachydactyly but no endocrinopathy, whereas the other manifests brachydactyly, obesity, and target tissue resistance to thyrotropin and parathyroid hormone (PTH). Levels of the alpha-subunit of the G protein (Gsalpha) were reduced in erythrocyte membranes from both girls and a nonsense mutation (Q12X) in exon 1 of the GNAS1 gene was identified in genomic DNA from the mildly affected patient. Features of POH and AHO in two individuals suggest that these conditions share a similar molecular basis and pathogenesis and that isolated severe extraskeletal ossification may be another manifestation of Gsalpha deficiency.
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PMID:Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification. 1109 90

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 alpha-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 Gsalpha 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 betagamma subunit of Gsalpha protein, this mutation may impair Gs protein function. We report here one novel Gsalpha mutation, and note that mutations in Japanese patients with PHP-Ia are probably heterogeneous.
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PMID:Two mutations of the Gsalpha gene in two Japanese patients with sporadic pseudohypoparathyroidism type Ia. 1145 Aug 52

The heterotrimeric G protein G(s) couples hormone receptors (as well as other receptors) to the effector enzyme adenylyl cyclase and is therefore required for hormone-stimulated intracellular cAMP generation. Receptors activate G(s) by promoting exchange of GTP for GDP on the G(s) alpha-subunit (G(s)alpha) while an intrinsic GTPase activity of G(s)alpha that hydrolyzes bound GTP to GDP leads to deactivation. Mutations of specific G(s)alpha residues (Arg(201) or Gln(227)) that are critical for the GTPase reaction lead to constitutive activation of G(s)-coupled signaling pathways, and such somatic mutations are found in endocrine tumors, fibrous dysplasia of bone, and the McCune-Albright syndrome. Conversely, heterozygous loss-of-function mutations may lead to Albright hereditary osteodystrophy (AHO), a disease characterized by short stature, obesity, brachydactyly, sc ossifications, and mental deficits. Similar mutations are also associated with progressive osseous heteroplasia. Interestingly, paternal transmission of GNAS1 mutations leads to the AHO phenotype alone (pseudopseudohypoparathyroidism), while maternal transmission leads to AHO plus resistance to several hormones (e.g., PTH, TSH) that activate G(s) in their target tissues (pseudohypoparathyroidism type IA). Studies in G(s)alpha knockout mice demonstrate that G(s)alpha is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues (e.g., renal proximal tubule, the major site of renal PTH action), while being biallelically expressed in most other tissues. Disrupting mutations in the maternal allele lead to loss of G(s)alpha expression in proximal tubules and therefore loss of PTH action in the kidney, while mutations in the paternal allele have little effect on G(s)alpha expression or PTH action. G(s)alpha has recently been shown to be also imprinted in human pituitary glands. The G(s)alpha gene GNAS1 (as well as its murine ortholog Gnas) has at least four alternative promoters and first exons, leading to the production of alternative gene products including G(s)alpha, XLalphas (a novel G(s)alpha isoform that is expressed only from the paternal allele), and NESP55 (a chromogranin-like protein that is expressed only from the maternal allele). A fourth alternative promoter and first exon (exon 1A) located approximately 2.5 kb upstream of the G(s)alpha promoter is normally methylated on the maternal allele and transcriptionally active on the paternal allele. In patients with isolated renal resistance to PTH (pseudohypoparathyroidism type IB), the exon 1A promoter region has a paternal-specific imprinting pattern on both alleles (unmethylated, transcriptionally active), suggesting that this region is critical for the tissue-specific imprinting of G(s)alpha. The GNAS1 imprinting defect in pseudohypoparathyroidism type IB is predicted to decrease G(s)alpha expression in renal proximal tubules. Studies in G(s)alpha knockout mice also demonstrate that this gene is critical in the regulation of lipid and glucose metabolism.
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PMID:Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. 1158 48

We report the case of a 27-year old woman who presented hypocalcemia and hyperphosphoremia during her first pregnancy. Her phenotype was in favor of Albright's hereditary osteodystrophy: short stature, obesity, round face, brachymetacarpy and mental retardation. However, the diagnosis of pseudohypopara thyroidism type Ia was ruled out due to low PTH level (10 pg/ml). The patient's 22q11 microdeletion was suspected and identified because of the association of severe neonatal hypocalcemia, abnormal face and renal malformation in her children. Deletion 22q11 leads to various syndromes, including Di George syndrome, also referred to as CATCH 22 syndrome (Cardiac defect (C), Abnormal face (A), Thymic hypoplasia (T), Cleft palate (C) and Hypocalcemia (H)). Retrospectively, the patient presented with symptoms suggestive of CATCH 22: abnormal face, hypernasal voice suggestive of velopharyngeal insufficiency, mental retardation, recurrent otitis in childhood. It is also noteworthy that there was an idiopathic thrombocytopenic purpura. In conclusion, while the phenotype was suggestive of Albright's hereditary osteodystrophy, the constatation of a low PTH level would cast doubt on this diagnosis. Furthermore, the 22q11 microdeletion should be searched by FISH (Fluorescence In Situ Hybridization) in all patients with hypopara thyroidism of unknown origin, even in the absence of cardiac malformations. Finally, it seems that patients with CATCH 22 would be predisposed to auto-immune disease as a result of thymic dysfunction.
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PMID:[Pseudohypoparathyroidism or hypoparathyroidism? A misleading clinical presentation]. 1184 29


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