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Rajesh V Thakker - One of the best experts on this subject based on the ideXlab platform.
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familial hypocalciuric hypercalcemia type 1 and autosomal dominant hypocalcemia type 1 prevalence in a large healthcare population
American Journal of Human Genetics, 2020Co-Authors: Ridge Dershem, Fadil M. Hannan, Caroline M Gorvin, Rajesh V Thakker, Raghu Metpally, Sarathbabu Krishnamurthy, Diane T Smelser, David J Carey, Gerda E BreitwieserAbstract:The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were Hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism.
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Hypercalcemic disorders in children
Journal of Bone and Mineral Research, 2017Co-Authors: Victoria Stokes, Fadil M. Hannan, Morten F Nielsen, Rajesh V ThakkerAbstract:Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)-dependent or PTH-independent, and may be congenital or acquired. PTH-independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH-dependent hypercalcemia. Acquired causes of PTH-independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH-independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH-dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH-dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary Hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 American Society for Bone and Mineral Research.
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calcium sensing receptor casr mutations and disorders of calcium electrolyte and water metabolism
Best Practice & Research Clinical Endocrinology & Metabolism, 2013Co-Authors: Fadil M. Hannan, Rajesh V ThakkerAbstract:The extracellular calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that is expressed at multiple sites, including the parathyroids and kidneys. The human CASR gene, located on chromosome 3q21.1, encodes a 1078 amino acid protein. More than 230 different disease-causing mutations of the CaSR have been reported. Loss-of-function mutations lead to three Hypercalcemic disorders, which are familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism and primary hyperparathyroidism. Gain-of-function mutations, on the other hand, result in the hypocalcemic disorders of autosomal dominant hypocalcemia and Bartter syndrome type V. Moreover, autoantibodies directed against the extracellular domain of the CaSR have been found to be associated with FHH in some patients, and also in some patients with hypoparathyroidism that may be part of autoimmune polyglandular syndrome type 1. Studies of disease-causing CASR mutations have provided insights into structure–function relationships and highlighted intra-molecular domains that are critical for ligand binding, intracellular signaling, and receptor trafficking.
Fadil M. Hannan - One of the best experts on this subject based on the ideXlab platform.
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familial hypocalciuric hypercalcemia type 1 and autosomal dominant hypocalcemia type 1 prevalence in a large healthcare population
American Journal of Human Genetics, 2020Co-Authors: Ridge Dershem, Fadil M. Hannan, Caroline M Gorvin, Rajesh V Thakker, Raghu Metpally, Sarathbabu Krishnamurthy, Diane T Smelser, David J Carey, Gerda E BreitwieserAbstract:The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were Hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism.
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Hypercalcemic disorders in children
Journal of Bone and Mineral Research, 2017Co-Authors: Victoria Stokes, Fadil M. Hannan, Morten F Nielsen, Rajesh V ThakkerAbstract:Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)-dependent or PTH-independent, and may be congenital or acquired. PTH-independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH-dependent hypercalcemia. Acquired causes of PTH-independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH-independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH-dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH-dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary Hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 American Society for Bone and Mineral Research.
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Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation.
JCI insight, 2017Co-Authors: Sarah A. Howles, Fadil M. Hannan, Caroline M Gorvin, Sian E. Piret, Anju Paudyal, Michelle Stewart, Tertius Hough, M. Andrew Nesbit, Sara Wells, Stephen D.m. BrownAbstract:Loss-of-function mutations of GNA11, which encodes G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in familial hypocalciuric hypercalcemia type 2 (FHH2). FHH2 is characterized by hypercalcemia, inappropriately normal or raised parathyroid hormone (PTH) concentrations, and normal or low urinary calcium excretion. A mouse model for FHH2 that would facilitate investigations of the in vivo role of Gα11 and the evaluation of calcimimetic drugs, which are CaSR allosteric activators, is not available. We therefore screened DNA from > 10,000 mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for GNA11 mutations and identified a Gα11 variant, Asp195Gly (D195G), which downregulated CaSR-mediated intracellular calcium signaling in vitro, consistent with it being a loss-of-function mutation. Treatment with the calcimimetic cinacalcet rectified these signaling responses. In vivo studies showed mutant heterozygous (Gna11+/195G) and homozygous (Gna11195G/195G) mice to be Hypercalcemic with normal or increased plasma PTH concentrations and normal urinary calcium excretion. Cinacalcet (30mg/kg orally) significantly reduced plasma albumin-adjusted calcium and PTH concentrations in Gna11+/195G and Gna11195G/195G mice. Thus, our studies have established a mouse model with a germline loss-of-function Gα11 mutation that is representative for FHH2 in humans and demonstrated that cinacalcet can correct the associated abnormalities of plasma calcium and PTH.
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calcium sensing receptor casr mutations and disorders of calcium electrolyte and water metabolism
Best Practice & Research Clinical Endocrinology & Metabolism, 2013Co-Authors: Fadil M. Hannan, Rajesh V ThakkerAbstract:The extracellular calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that is expressed at multiple sites, including the parathyroids and kidneys. The human CASR gene, located on chromosome 3q21.1, encodes a 1078 amino acid protein. More than 230 different disease-causing mutations of the CaSR have been reported. Loss-of-function mutations lead to three Hypercalcemic disorders, which are familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism and primary hyperparathyroidism. Gain-of-function mutations, on the other hand, result in the hypocalcemic disorders of autosomal dominant hypocalcemia and Bartter syndrome type V. Moreover, autoantibodies directed against the extracellular domain of the CaSR have been found to be associated with FHH in some patients, and also in some patients with hypoparathyroidism that may be part of autoimmune polyglandular syndrome type 1. Studies of disease-causing CASR mutations have provided insights into structure–function relationships and highlighted intra-molecular domains that are critical for ligand binding, intracellular signaling, and receptor trafficking.
Nicholas Frank - One of the best experts on this subject based on the ideXlab platform.
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Diagnosis and treatment of confirmed and suspected primary hyperparathyroidism in equids: 17 cases (1999–2016)
Equine veterinary journal, 2019Co-Authors: E. B. Gorenberg, Amy L. Johnson, K. G. Magdesian, Francois-rene Bertin, L. R. R. Costa, M.j.p. Theelen, S. A. Durward-akhurst, C. Cruz Villagrán, H.b. Carslake, Nicholas FrankAbstract:Background: Primary hyperparathyroidism is uncommon in equids. Objectives: To describe the diagnostic findings and efficacy of treatment in equids with primary hyperparathyroidism. Study design: Retrospective case series describing 16 horses and one mule. Methods: Cases were identified by retrospective review of records at Cornell University and via an ACVIM listserv query. Inclusion criteria were an equid with hypercalcemia, normal renal function and high parathyroid hormone (PTH) or histopathological diagnosis of a parathyroid adenoma. Equids with normal PTH and PTH-related protein (PTHrP) in the face of hypercalcemia were included as suspect cases. Results: The most common presenting complaints were weight loss (12/17) and hypercalcemia (10/17). PTH was above reference range in 12/17 cases. Suspected parathyroid tumours were localised in 12/14 equids imaged using ultrasonography alone (2/3), technetium 99m Tc sestamibi scintigraphy alone (1/1) or both modalities (9/10). Three horses did not have imaging performed. Surgical exploration successfully excised tumours in six of 10 cases. Five were located at the thoracic inlet, and surgery resulted in complete cure. One tumour was excised from the thyroid lobe, and the horse remained Hypercalcemic. Four other cases explored surgically, four treated medically and three that were not treated also remained Hypercalcemic. Main limitations: The small study size prohibited statistical analysis. Conclusions: Parathyroid adenomas in equids can be successfully localised with ultrasonography and scintigraphy. Surgical excision appears more likely to be successful for single gland disease at the thoracic inlet.
Edward M. Brown - One of the best experts on this subject based on the ideXlab platform.
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anti parathyroid and anti calcium sensing receptor antibodies in autoimmune hypoparathyroidism
Endocrinology and Metabolism Clinics of North America, 2009Co-Authors: Edward M. BrownAbstract:The parathyroid glands are an infrequent target for autoimmunity, the exception being autoimmune polyglandular syndrome type 1, in which autoimmune hypoparathyroidism is the rule. Antibodies that are directed against the parathyroid cell surface calcium-sensing receptor (CaSR) have recently been recognized to be present in the serum of patients with autoimmune hypoparathyroidism. In some individuals, these anti-CaSR antibodies have also been shown to produce functional activation of the receptor, suggesting a direct pathogenic role in hypocalcemia. Additionally, a few Hypercalcemic patients with autoimmune hypocalciuric hypercalcemia owing to anti-CaSR antibodies that inhibit receptor activation have now been identified. Other novel parathyroid autoantigens are starting to be elucidated, suggesting that new approaches to treatment, such as CaSR antagonists or agonists (calcilytics/calcimimetics), may be worthwhile.
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familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor
The Journal of Clinical Endocrinology and Metabolism, 2000Co-Authors: Tobias Carling, Edward M. Brown, Eva Szabo, Mei Bai, Peter Ridefelt, Gunnar Westin, Peter Gustavsson, Sunita Trivedi, Per Hellman, Niklas DahlAbstract:Familial hyperparathyroidism (HPT), characterized by hypercalcemia and hypercalciuria, and familial benign hypocalciuric hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. The calcium-sensing receptor (CaR) regulates PTH secretion and renal calcium excretion. Heterozygous inactivating mutations of the gene cause FHH, whereas CaR gene mutations have not been demonstrated in HPT. In a kindred with 20 affected individuals, the Hypercalcemic disorder segregated with inappropriately higher serum PTH and magnesium levels and urinary calcium levels than in unaffected members. Subtotal parathyroidectomy revealed parathyroid gland hyperplasia/adenoma and corrected the biochemical signs of the disorder in seven of nine individuals. Linkage analysis mapped the condition to markers flanking the CaR gene on chromosome 3q. Sequence analysis revealed a mutation changing phenylalanine to leucine at codon 881 of the CaR gene, representing the first identified point mutation located within the cytoplasmic tail of the CaR. A construct of the mutant receptor (F881L) was expressed in human embryonic kidney cells (HEK 293), and demonstrated a right-shifted dose-response relationship between the extracellular and intracellular calcium concentrations. The Hypercalcemic disorder of the present family is caused by an inactivating point mutation in the cytoplasmic tail of the CaR and displays clinical characteristics atypical of FHH and primary HPT.
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markedly reduced activity of mutant calcium sensing receptor with an inserted alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism
Journal of Clinical Investigation, 1997Co-Authors: Mei Bai, Edward M. Brown, Sunita Trivedi, N Janicic, Stephen J Quinn, David E C Cole, Geoffrey N HendyAbstract:Missense mutations have been identified in the coding region of the extracellular calcium-sensing receptor (CASR) gene and cause human autosomal dominant hypo- and Hypercalcemic disorders. The functional effects of several of these mutations have been characterized in either Xenopus laevis oocytes or in human embryonic kidney (HEK293) cells. All of the mutations that have been examined to date, however, cause single putative amino acid substitutions. In this report, we studied a mutant CASR with an Alu-repetitive element inserted at codon 876, which was identified in affected members of families with the Hypercalcemic disorders, familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), to understand how this insertion affects CASR function. After cloning of the Alu-repetitive element into the wild-type CASR cDNA, we transiently expressed the mutant receptor in HEK293 cells. Expression of mutant and wild-type receptors was assessed by Western analysis, and the effects of the mutation on extracellular calcium (Ca2+(o)) and gadolinium (Gd3+(o)) elicited increases in the cytosolic calcium concentration (Ca2+(i)) were examined in fura-2-loaded cells using dual wavelength fluorimetry. The insertion resulted in truncated receptor species that had molecular masses some 30 kD less than that of the wild-type CASR and exhibited no Ca2+(i) responses to either Ca2+(o) or Gd3+(o). A similar result was observed with a mutated CASR truncated at residue 876. However, the Alu mutant receptor had no impact on the function of the coexpressed wild-type receptor. Interestingly, the Alu mutant receptor demonstrated decreased cell surface expression relative to the wild-type receptor, whereas the CASR (A877stop) mutant exhibited increased cell surface expression. Thus, like the missense mutations that have been characterized to date in families with FHH, the Alu insertion in this family is a loss-of-function mutation that produces hypercalcemia by reducing the number of normally functional CASRs on the surface of parathyroid and kidney cells. In vitro transcription of exon 7 of the CASR containing the Alu sequence yielded the full-length mutant product and an additional shorter product that was truncated due to stalling of the polymerase at the poly(T) tract. In vitro translation of the mutant transcript yielded three truncated protein products representing termination in all three reading frames at stop codons within the Alu insertion. Thus sequences within the Alu contribute to slippage or frameshift mutagenesis during transcription and/or translation.
Michele Sacco - One of the best experts on this subject based on the ideXlab platform.
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calcium sensing receptor casr mutations in Hypercalcemic states studies from a single endocrine clinic over three years
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Vito Guarnieri, Betty Y L Wong, Lucie Canaff, Alfredo Scillitani, Claudia Battista, Lucia Anna Muscarella, Francisco H J Yun, Angelantonio Notarangelo, Leonardo Dagruma, Michele SaccoAbstract:Context: Inactivating mutations of the calcium-sensing receptor (CASR) are implicated in different Hypercalcemic syndromes, including familial hypocalciuric hypercalcemia (FHH), primary hyperparathyroidism (PHPT), and familial isolated hyperparathyroidism (FIHP). However, molecular diagnostics applied to large nonselected Hypercalcemic cohorts from a single center have not been reported. Objective: Our objective was to describe the prevalence, type, and potential pathogenicity of CASR mutations in a series of cases with FHH (n = 17), PHPT (n = 165), and FIHP (n = 3) and controls (n = 198) presenting at a single endocrine clinic. Subjects: All were prospectively evaluated at the “Casa Sollievo della Sofferenza” Hospital in southern Italy over a 3-yr period. Methods: CASR screening was conducted by denaturing HPLC. The variant CASRs were functionally characterized by transient transfection studies in kidney cells in vitro. Results: A single novel missense variant was identified in one PHPT case. However, in...