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)

We have previously demonstrated that genetically based leptin deficiency due to a missense leptin gene mutation in a highly consanguineous extended Turkish pedigree is associated with morbid obesity and hypogonadism. We have now performed detailed assessments of endocrine, sympathetic, and immune function. We have also identified a new adult female homozygous patient in this extended family who is severely obese and amenorrheic. In this family all wild-type and heterozgous individuals have normal body weight. Seven obese members of this family, whom we presume to have been leptin deficient, died during childhood. There are several findings that indicate potentially novel targets for leptin action in humans. Four homozygous patients (1 adult male, 2 adult females, and 1 child) have sympathetic system dysfunction, whereas all heterozygous subjects have normal sympathetic system function. Despite sympathetic system dysfunction and postural hypotension, 1 of 3 homozygous adult patients has impaired renin-aldosterone function. The patients also exhibit alterations in GH and PTH-calcium function, and 1 of them has decreased bone mineral density. Despite their obesity, these patients do not have risk factors for cardiovascular disease, such as hypertension, impairments in lipid metabolism, or hyperleptinemia [corrected]. These data support the hypothesis that the obese may have central, but not peripheral, resistance to the effects of leptin and that hyperleptinemia [corrected] may mediate the cardiovascular morbidity of the obese who are not leptin deficient. Furthermore, these data indicate that there may be several new targets for leptin action in human physiology. Such new targets may lead to novel pharmacological strategies for the use of leptin agonists and antagonists in the treatment of human disease. All 19 normal weight individuals in this family are alive, whereas 7 of 11 obese individuals died in childhood after infections. The odds ratio for mortality in the context of this obesity phenotype is 25.4, indicating that this mutation severely impairs key biological functions during childhood, negatively impacting on survival. We found that only the obese child in this family had thyroid function abnormalities. The oldest homozygous female patient started to menstruate, albeit with a luteal phase defect, 7 months ago, after a delay of over 20 yr, whereas the younger adult subjects are still hypogonadic. Thus, we conclude that due to their long life span, humans who survive the negative effects of leptin deficiency during childhood can, in contrast to ob/ob mice, over decades compensate some of the effects of leptin deficiency on immunity and endocrine function through mechanisms that remain to be elucidated.
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PMID:Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. 1183 53

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

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

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

Pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO) are not interchangeable terms. AHO describes a constellation of physical features, including short adult stature, obesity, brachydactyly, and ectopic ossifications. PHP means end-organ resistance to PTH and is subclassified into types Ia, Ib, and Ic and type II. Pseudopseudohypoparathyroidism (PPHP) is a term used for individuals with AHO who have normal end-organ responses to PTH. Both the PHPIa and PPHP forms of AHO result from heterozygous deactivating mutations in the GNAS1 gene associated with a 50% reduction in bioactivity of the Gsalpha protein that it encodes. The GNAS1 gene is subject to tissue-specific genomic imprinting. Patients with mutations on their maternally derived allele are likely to have associated PHPIa, whereas mutations on the paternal allele usually cause PPHP. Isolated PTH resistance (PHPIb) can result from mutations within the GNAS1 gene but is more commonly caused by epigenetic imprinting abnormalities affecting the upstream exon 1A. The causes of PHP type Ic and PHP type II are not yet clear, and the latter is likely to be heterogeneous.
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PMID:Albright's hereditary osteodystrophy and pseudohypoparathyroidism. 1254 Nov 84

Patients with primary hyperparathyroidism (PHPT) have an increased cardiovascular morbidity and mortality. Elevated serum calcium and/or PTH may directly contribute to vascular tissue damage, but the role of classic factors for atherosclerosis has not fully been evaluated in this disease. The aim of our study was to dissect the potential effect of hypercalcemia and/or high PTH from that of major cardiovascular risk factors (i.e. diabetes mellitus, hyperlipidemia, hypertension, obesity, smoking habit) on the carotid artery structure of patients with PHPT. Twenty-six consecutive patients with PHPT [subdivided into two groups according to the absence (n = 10) or the presence (n = 16) of one or more risk factors] and 15 normocalcemic healthy subjects as controls were studied. At ultrasonography, a significant increase (P < 0.001) of carotid mean and maximum intima-media thickness, as well as a significant reduction of lumen diameter (P < 0.05) were found in the PHPT group with risk factors, compared with the other two groups. This suggests that hypercalcemia and/or PTH elevation per se are not determinant of carotid atherosclerosis in PHPT, and that increased cardiovascular mortality and morbility in this disease is attributable to the combined presence of classic cardiovascular risk factors.
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PMID:Ultrasound evaluation of carotid artery in primary hyperparathyroidism. 1272 60

Genetic analysis of the GNAS gene was performed in a patient with idiopathic renin-dependent hypertension, PTH resistance, and Albright's hereditary osteodystrophy-like characteristics such as a round face, short stature, obesity, and mental retardation (IQ, 49). Mutational analysis showed no mutations in exons 1-13 or in any exon-intron boundary. However, methylation-status analysis revealed a bialleic methylation defect in GNAS exon 1A, indicating that a GNAS-imprinting defect is the cause of her PTH resistance, as commonly observed in pseudohypoparathyroidism type IB. The imprinting defect, however, could not explain her renin-dependent hypertension and Albright's hereditary osteodystrophy-like phenotype. There are many types of X-linked mental retardation. Syndromic X-linked mental retardation, such as X-linked alpha-thalassemia mental retardation syndrome and Rett syndrome, is reportedly associated with abnormal imprinting. To further investigate this unexplained phenotype, we tested whether this patient showed skewed X-inactivation (SXI) presumably as a result of postinactivation selection against cells with a mutated gene on the active X-chromosome. Completely SXI was observed in the DNA from her leukocytes, urinary sediment, and renal tissue. A mutation of the X-chromosome might be correlated with this phenotype because of a close association between completely SXI and X-chromosomal mutation.
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PMID:Completely skewed X-inactivation in a mentally retarded young female with pseudohypoparathyroidism type IB and juvenile renin-dependent hypertension. 1284 41

Albright hereditary osteodystrophy (AHO) is a genetic disorder caused by heterozygous inactivating mutations in GNAS1, the gene encoding the alpha-chain of G(s), and is associated with short stature, obesity, brachydactyly, and sc ossifications. AHO patients with GNAS1 mutations on maternally inherited alleles also manifest resistance to multiple hormones (e.g. PTH, TSH, LH, FSH), a variant termed pseudohypoparathyroidism (PHP) type 1a, due to paternal imprinting of G alpha(s) transcripts in specific tissues. Recent evidence has shown that G alpha(s) transcripts are also imprinted in the pituitary somatotrophs that secrete GH. Because this imprinting could influence GHRH-dependent stimulation of somatotrophs, we hypothesized that maternally inherited GNAS1 mutations would impair GH secretion. We studied GH status in 13 subjects with PHP type 1a. GH responses to arginine/L-dopa and arginine/GHRH were deficient in nine subjects, all of whom were obese and had low serum concentrations of IGF-I. By contrast, none of the four GH-sufficient subjects were obese, and all had normal IGF-I levels. Our data indicate that GH deficiency is common (69%) in PHP type 1a and may contribute to the obesity and short stature typical of AHO. We propose that GH status be evaluated in all patients with PHP type 1a.
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PMID:Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. 1297 Feb 61

Several previous reports of small cohorts have found significantly higher serum 1,25-dihydroxy vitamin D (1,25-vit D) in obese compared with nonobese whites. Based on these reports and on recent in vitro studies of adipocytes which suggest that administration of 1,25-vit D can stimulate lipogenesis and inhibit lipolysis, some investigators have proposed that high 1,25-vit D may play a role in promoting or maintaining adipocyte triglyceride stores in obese adults. To test the hypothesis that obesity is commonly associated with increased 1,25-vit D, we examined the relationships between calciotropic hormones and body adiposity in a large cohort of healthy adults. Serum intact PTH, 25-hydroxy vitamin D, and 1,25-vit D were measured in the postabsorptive state in 302 healthy adults who were Caucasian (n = 190; 71% female), African-American (n = 84; 89% female), and of other race/ethnicity (n = 28; 61% female). Results from the 154 obese subjects [body mass index (BMI) 37.3 +/- 5.8 kg/m(2); range, 30.1-58.2 kg/m(2)] were compared with those from 148 nonobese (BMI 25.6 +/- 2.9 kg/m(2); range, 18.0-29.9 kg/m(2)) age-, race-, and sex-matched participants. Body composition was measured by dual energy x-ray absorptiometry. Serum intact PTH was positively correlated with both BMI (r = 0.42; P < 0.0001) and body fat mass (r = 0.37; P < 0.0001). Serum 25-hydroxy vitamin D was negatively correlated with BMI (r = -0.4; P < 0.0001) and body fat mass (r = -0.41; P < 0.0001). Serum 1,25-vit D was also negatively correlated with BMI (r = -0.26; P < 0.0001) and body fat mass (r = -0.25; P = 0.0001). Serum 1,25-vit D was significantly lower in obese than nonobese subjects (105.7 +/- 41.1 vs. 124.8 +/- 36.7 pmol/liter; P < 0.0001) in both Caucasian and African-American adults. We conclude that, because 1,25-vit D concentrations fall with increasing adiposity, it appears unlikely that elevation in 1,25-vit D is an important hormonal mechanism causing or maintaining obesity in adults.
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PMID:The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. 1500 9


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