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Mutation Research. Reviews in Mutation... 2024GNAS (guanine nucleotide-binding protein, alpha stimulating) is an imprinted gene that encodes Gα, the α subunit of the heterotrimeric stimulatory G protein. This... (Review)
Review
BACKGROUND
GNAS (guanine nucleotide-binding protein, alpha stimulating) is an imprinted gene that encodes Gα, the α subunit of the heterotrimeric stimulatory G protein. This subunit mediates the signalling of a diverse array of G protein-coupled receptors (GPCRs), including the melanocortin 4 receptor (MC4R) that serves a pivotal role in regulating food intake, energy homoeostasis, and body weight. Genetic or epigenetic alterations in GNAS are known to cause pseudohypoparathyroidism in its different subtypes and have been recently associated with isolated, early-onset, severe obesity. Given the diverse biological functions that Gα serves, multiple molecular mechanisms involving various GPCRs, such as MC4R, β- and β-adrenoceptors, and corticotropin-releasing hormone receptor, have been implicated in the pathophysiology of severe, early-onset obesity that results from genetic or epigenetic GNAS changes.
SCOPE OF REVIEW
This review examines the structure and function of GNAS and provides an overview of the disorders that are caused by defects in this gene and may feature early-onset obesity. Moreover, it elucidates the potential molecular mechanisms underlying Gα deficiency-induced early-onset obesity, highlighting some of their implications for the diagnosis, management, and treatment of this complex condition.
MAJOR CONCLUSIONS
Gα deficiency is an underappreciated cause of early-onset, severe obesity. Therefore, screening children with unexplained, severe obesity for GNAS defects is recommended, to enhance the molecular diagnosis and management of this condition.
Topics: Humans; GTP-Binding Protein alpha Subunits, Gs; Chromogranins; Epigenesis, Genetic; Obesity; Animals; Pseudohypoparathyroidism; Mutation; Receptor, Melanocortin, Type 4; Age of Onset
PubMed: 38103632
DOI: 10.1016/j.mrrev.2023.108487 -
Annals of Dermatology Nov 2023
PubMed: 38061755
DOI: 10.5021/ad.22.120 -
JCEM Case Reports Nov 2023Fahr syndrome is a rare neurologic disorder, usually affecting young and middle-aged adults, that can present with symptoms ranging from extrapyramidal to...
Fahr syndrome is a rare neurologic disorder, usually affecting young and middle-aged adults, that can present with symptoms ranging from extrapyramidal to neuropsychiatric abnormalities. Pseudohypoparathyroidism (PHP), characterized by parathyroid hormone (PTH)-resistance or PTH-unresponsiveness at target organs, is associated with Fahr syndrome and typically presents with hypocalcemia. The following case presents a 39-year-old-woman with PHP complicated by symptomatic hypocalcemia, hypokalemia, and movement disturbances, who had computed tomography imaging showing basal ganglia calcifications consistent with Fahr syndrome. She initially presented with headache and was hospitalized for hypertensive emergency and severe hypocalcemia. Examination, including the neurologic examination, was unrevealing aside from hypertension and central adiposity. Laboratory tests were consistent with PHP, showing hypocalcemia with elevated PTH, and negative for hyperaldosteronism. Management of hypocalcemia consisted of intravenous calcium infusion, oral calcium carbonate, oral vitamin D3, and oral calcitriol. Patients with severe hypocalcemia and elevated PTH who present with new neurological symptoms despite normal general neurologic examination may warrant consideration for brain imaging to evaluate for Fahr syndrome. Further investigations are necessary to determine the prevalence of Fahr syndrome and hypokalemia in patients with PHP, explore if these findings are significantly associated with PHP-1b subtype, and ultimately inform potential new screening pathways for these patients.
PubMed: 38045865
DOI: 10.1210/jcemcr/luad147 -
Orphanet Journal of Rare Diseases Nov 2023Pseudohypoparathyroidism type 1 (PHP1) is a rare disease featuring hypocalcemia and elevated PTH level. Though disturbed calcium and phosphorus metabolism under PTH...
BACKGROUND
Pseudohypoparathyroidism type 1 (PHP1) is a rare disease featuring hypocalcemia and elevated PTH level. Though disturbed calcium and phosphorus metabolism under PTH resistant have been widely studied, glucolipid metabolism abnormalities observed in PHP1 patients have received little attention. The aim of this research is to explore the glucolipid metabolism features in a rather large cohort of PHP1 patient. In the current study, PHP1 patients and primary hyperparathyroidism patients as well as normal control were recruited for the investigation. Glucolipid metabolic indices as well as the level of four adipokines were examined.
RESULTS
A total of 49 PHP1 patients, 64 PHPT patients and 30 healthy volunteers were enrolled. A trend of higher HOMA-β index was found in PHP1 patients than normal controls (median 97.08% vs 68.19%, p = 0.060). Both the PHP1 and PHPT group presented with significantly lower TNFα level compared to normal controls (average 10.74 pg/ml and 12.53 pg/ml vs 15.47 pg/ml, p = 0.002 and 0.041, respectively). FGF21 level was significantly higher in PHPT group than in PHP1 group (median 255.74 pg/ml vs 167.46 pg/ml, p = 0.019). No significant difference in glucolipid metabolic indices and adipokines was found between PHP1A or PHP1B patients and normal controls, while overweight/obese PHP1 patients tended to have higher leptin than normal-BMI cases (p = 0.055). Multiple linear regression analysis showed BMI rather than PTH or HOMA-IR to be an independent variable of leptin in PHP1.
CONCLUSION
Metabolic stress given upon especially overweight PHP1 patients may resulted in possible β-cell compensation. Elevated TNFα may be related with hyper-PTH level regardless of calcium level.
Topics: Humans; Calcium; Leptin; Adipokines; Tumor Necrosis Factor-alpha; Overweight; Pseudohypoparathyroidism
PubMed: 38017461
DOI: 10.1186/s13023-023-02979-w -
The Journal of International Medical... Nov 2023We report a 15-year-old Chinese girl who presented with intermittent seizure episodes and had been misdiagnosed as having idiopathic epilepsy 5 years previously....
We report a 15-year-old Chinese girl who presented with intermittent seizure episodes and had been misdiagnosed as having idiopathic epilepsy 5 years previously. Laboratory testing revealed hypocalcemia, hyperphosphatemia, and a high parathyroid hormone (PTH) concentration. She was subsequently shown to have pseudohypoparathyroidism type Ib (PHPIb) based on the results of methylation analysis of the gene, which showed a loss of methylation of the differentially methylated regions (DMR) of , , and ; and a gain of methylation of the DMR of the GNAS-NESP55 region. We adjusted the patient's medication by prescribing calcium and calcitriol supplements, and gradually reduced the doses of antiepileptic drugs, until they had been completely discontinued. As a result, the patient did not experience any further seizures or epileptiform symptoms; and had normal plasma calcium, phosphorus, and 25-hydroxyvitamin D concentrations and 24-hour urinary calcium excretion. In addition, her PTH concentration gradually normalized over 12 months, and no urinary stones were found on ultrasonographic examination. In conclusion, the clinical presentation of PHP is complex, and the condition is often misdiagnosed. The diagnosis and follow-up of the present patient have provide valuable insights that should contribute to informed clinical decision-making and the implementation of appropriate treatment strategies.
Topics: Humans; Female; Adolescent; GTP-Binding Protein alpha Subunits, Gs; DNA Methylation; Calcium; Follow-Up Studies; Chromogranins; Pseudohypoparathyroidism; Parathyroid Hormone; Epilepsy; Diagnostic Errors
PubMed: 38017366
DOI: 10.1177/03000605231215202 -
Journal of Molecular Endocrinology Jan 2024Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G... (Review)
Review
Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. Thus, pseudohypoparathyroidism type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal GNAS exons 1-13 resulting in characteristic abnormalities referred to as Albright's hereditary osteodystrophy (AHO) that are associated with resistance to several agonist ligands, particularly to parathyroid hormone (PTH), thereby leading to hypocalcemia and hyperphosphatemia. GNAS mutations involving the paternal Gsα exons also cause most of these AHO features, but without evidence for hormonal resistance, hence the term pseudopseudohypoparathyroidism (PPHP). Autosomal dominant pseudohypoparathyroidism type Ib (PHP1B) due to maternal GNAS or STX16 mutations (deletions, duplications, insertions, and inversions) is associated with epigenetic changes at one or several differentially methylated regions (DMRs) within GNAS. Unlike the inactivating Gsα mutations that cause PHP1A and PPHP, hormonal resistance is caused in all PHP1B variants by impaired Gsα expression due to loss of methylation at GNAS exon A/B, which can be associated in some familial cases with epigenetic changes at the other maternal GNAS DMRs. The genetic defect(s) responsible for sporadic PHP1B, the most frequent variant of this disorder, remain(s) unknown for the majority of patients. However, characteristic epigenetic GNAS changes can be readily detected that include a gain of methylation at the neuroendocrine secretory protein (NESP) DMR. Multiple genetic or epigenetic GNAS abnormalities can thus impair Gsα function or expression, consequently leading to inadequate cAMP-dependent signaling events downstream of various Gsα-coupled receptors.
Topics: Humans; Chromogranins; Pseudohypoparathyroidism; GTP-Binding Protein alpha Subunits, Gs; Epigenesis, Genetic; DNA Methylation
PubMed: 37965945
DOI: 10.1530/JME-23-0104 -
Frontiers in Endocrinology 2023is a complex locus characterized by multiple transcripts and an imprinting effect. It orchestrates a variety of physiological processes via numerous signaling pathways.... (Review)
Review
is a complex locus characterized by multiple transcripts and an imprinting effect. It orchestrates a variety of physiological processes via numerous signaling pathways. Human diseases associated with the gene encompass fibrous dysplasia (FD), Albright's Hereditary Osteodystrophy (AHO), parathyroid hormone(PTH) resistance, and Progressive Osseous Heteroplasia (POH), among others. To facilitate the study of the locus and its associated diseases, researchers have developed a range of mouse models. In this review, we will systematically explore the locus, its related signaling pathways, the bone diseases associated with it, and the mouse models pertinent to these bone diseases.
Topics: Animals; Mice; Humans; GTP-Binding Protein alpha Subunits, Gs; Chromogranins; Pseudohypoparathyroidism; Bone Diseases, Metabolic; Ossification, Heterotopic
PubMed: 37920253
DOI: 10.3389/fendo.2023.1255864 -
JCEM Case Reports Jul 2023PTH resistance is characterized by hypocalcemia and hyperphosphatemia in the presence of elevated PTH concentrations, resulting in pseudohypoparathyroidism, which is...
PTH resistance is characterized by hypocalcemia and hyperphosphatemia in the presence of elevated PTH concentrations, resulting in pseudohypoparathyroidism, which is subdivided into different types according to its different pathogenesis and phenotype. PTH receptor is the alpha subunit of stimulatory G protein (Gα)-coupled receptor. Pathogenic variants of GNAS gene, encoding for Gα, lead to reduced Gα function and PTH resistance. We report a patient with PHP type 1a, with no documented evidence of hypocalcemia, presenting with AHO phenotype and multihormone resistance to PTH, TSH, and GnRH. Her genetic testing showed a novel heterozygous pathogenic variants, a c.934T > G change in exon 11 in adenylate cyclase stimulatory G protein that has not been reported in the literature so far.
PubMed: 37908988
DOI: 10.1210/jcemcr/luad088 -
SAGE Open Medical Case Reports 2023Pseudohypoparathyroidism is a terminology used to describe a group of metabolic disorders characterized by parathyroid hormone resistance. Patients with...
Pseudohypoparathyroidism is a terminology used to describe a group of metabolic disorders characterized by parathyroid hormone resistance. Patients with pseudohypoparathyroidism have hypocalcemia, hyperphosphatemia, and elevated serum parathyroid hormone. This methylation defect leads to signaling abnormalities in the parathyroid hormone and parathyroid hormone-related peptide receptor. We present a 40-year-old African American male who was referred to our endocrinology clinic for hypocalcemia. On physical examination, his body mass index was 34.3 kg/m and he was found to have a round face, and several subcutaneous nodules on his scalp, hands, and legs. Laboratory findings revealed hypocalcemia, hyperphosphatemia, and elevated levels of intact parathyroid hormone and thyroid stimulating hormone (TSH). His hand X-ray showed brachydactyly of all metacarpal bones, and soft tissue calcifications. Brain CT indicated dense calcifications in the subcortical region, bilateral basal ganglia, bilateral thalami, bilateral cerebellum and vermis, and soft tissue calcifications in the scalp. The "inactivating parathyroid hormone/parathyroid hormone-related peptide signaling disorder" diagnostic approach suggested by the Euro pseudohypoparathyroidism network was applied to the patient, who was diagnosed with parathyroid hormone signaling disorder. Compared to the old pseudohypoparathyroidism classification and the 2018 Pseudohypoparathyroidism International Consensus Statement Report, the inactivating parathyroid hormone/parathyroid hormone-related peptide signaling disorder cluster classification appears to be more flexible, and easier to use. It also accommodates future inclusion of genetic mutations associated with hormonal signaling disorders. Adoption of the inactivating parathyroid hormone/parathyroid hormone-related peptide signaling disorder classification remains limited, and further larger studies are needed to compare the three approaches.
PubMed: 37860280
DOI: 10.1177/2050313X231205776 -
Frontiers in Endocrinology 2023The serum calcium (Ca)-to-phosphorus (P) ratio has been proposed to identify patients with primary hyperparathyroidism and chronic hypoparathyroidism (HPT), but it has... (Observational Study)
Observational Study
OBJECTIVE
The serum calcium (Ca)-to-phosphorus (P) ratio has been proposed to identify patients with primary hyperparathyroidism and chronic hypoparathyroidism (HPT), but it has never been tested in pseudohypoparathyroidism (PHP). The aim of this study was to test the performance of Ca/P ratio in PHP diagnosis compared with that in healthy subjects and patients with HPT for differential diagnosis.
DESIGN
A retrospective, cross-sectional, and observational study was carried out.
METHODS
Serum Ca, P, creatinine, parathyroid hormone (PTH), and albumin were collected. Ca and P were expressed in mmol/L. Ca/P diagnostic performance was evaluated by receiver operating characteristic curve, sensitivity, specificity, and accuracy.
RESULTS
A total of 60 patients with PHP, 60 patients with HPT, and 120 controls were enrolled. The Ca/P ratio was lower in patients with PHP and HPT than that in controls (p < 0.0001). The cutoff of 1.78 (2.32 if Ca and P measured in mg/dL) for Ca/P ratio could identify patients with PHP and HPT among the entire cohort (sensitivity and specificity of 76%). No valid cutoff of Ca/P was found to distinguish patients with PHP from patients with HPT; in this case, PTH above 53.0 ng/dL identified patients with PHP (sensitivity and specificity of 100%). The index (Ca/P × PTH) above 116 ng/L recognized patients with PHP from controls (sensitivity of 84.7% and specificity of 87.4%), whereas (Ca/P × PTH) below 34 ng/L recognized patients with HPT from controls (sensitivity of 88.9% and specificity of 90.8%).
CONCLUSIONS
The Ca/P ratio below 1.78 (2.32 CU) is highly accurate to identify patients with PHP and HPT, although it is not reliable to differentiate these two conditions. The index (Ca/P × PTH) is excellent to specifically recognize PHP or HPT from healthy subjects.
Topics: Humans; Calcium; Retrospective Studies; Cross-Sectional Studies; Pseudohypoparathyroidism; Parathyroid Hormone; Hypoparathyroidism; Phosphorus
PubMed: 37854194
DOI: 10.3389/fendo.2023.1268704