Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype.

Pollak, Martin R.; Chou, Yah-Huei; Marx, Stephen J.; Steinmann, Beat; Cole, David E. C.; Brandi, Maria Luisa; Papapoulos, Socrates E.; Menko, Fred H.; Hendy, Geoffrey N.; Brown, Edward M.

doi:10.1172/jci117062

Cited by 264 publications

(98 citation statements)

References 20 publications

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“…NSHPT (76,77) represents the most severe expression of familial hypocalciuric hypercalcemia (68). In most patients in which mutations were found in the CASR, the two gene copies are mutated, with both parents having passed on a mutated copy and presenting with FHH.…”

Section: Neonatal Several Hyperparathyroidismmentioning

confidence: 99%

“…The gene dosage effect is clear in most FHH cases, with one mutated gene copy resulting in FHH with mild hypercalcemia and two mutated copies resulting in NSHPT, a more severe phenotype that manifests very early in life with severe hypercalcemia, bone demineralization and failure to thrive (68). However, the three cases of de novo NSHTP reported in the literature were heterozygous for missense mutations located in the extracellular domain, with only one mutated allele and no mutation found in the parents (79,104).…”

Section: Inactivating Mutationsmentioning

confidence: 99%

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The calcium-sensing receptor and related diseases

D’Souza-Li

2006

Arq Bras Endocrinol Metab

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The calcium-sensing receptor (CASR) adjusts the extracellular calcium set point regulating PTH secretion and renal calcium excretion. The receptor is expressed in several tissues and is also involved in other cellular functions such as proliferation, differentiation and other hormonal secretion. High extracellular calcium levels activate the receptor resulting in modulation of several signaling pathways depending on the target tissues. Mutations in the CASR gene can result in gain or loss of receptor function. Gain of function mutations are associated to Autossomal dominant hypocalcemia and Bartter syndrome type V, while loss of function mutations are associated to Familial hypocalciuric hypercalcemia and Neonatal severe hyperparathyroidism. More than one hundred mutations were described in this gene. In addition to calcium, the receptor also interacts with several ions and polyamines. The CASR is a potential therapeutic target to treatment of diseases including hyperparathyroidism and osteoporosis, since its interaction with pharmacological compounds results in modulation of PTH secretion. RESUMO O Receptor Sensor de Cálcio e Doenças Associadas.O receptor sensor de cálcio (CASR) ajusta o set point do cálcio extracelular através da regulação da secreção de PTH e da excreção renal de cál-cio. O receptor é expresso em diversos tecidos e também está envolvido em outras funções celulares como proliferação, diferenciação e secreção de outros hormônios. Concentrações altas de cálcio extracelular ativam o receptor resultando em modulação de inúmeras vias de sinais intracelulares dependendo do tecido-alvo. Mutações no gene do CASR podem resultar em ganho ou perda de função do receptor. Mutações com ganho de função são associadas à Hipocalcemia autossômica dominante e à Síndrome de Bartter tipo V, enquanto que mutações com perda de função são associadas à Hipercalcemia hipocalciúrica familiar e ao Hiperparatireoidismo neonatal grave. Mais de cem mutações foram descritas neste gene. Além do cálcio, o receptor também interage com inúmeros íons e poliaminas. CASR é um alvo terapêutico potencial para tratamento de doenças incluindo hiperparatireoidismo e osteoporose, pois a sua interação com compostos farmacológicos resulta em modulação da secreção de PTH. [Ca 2+ o ] sensing mechanism that results in changes in phosphoinositide turnover and cytosolic calcium to regulate PTH secretion (1). Extracellular calcium regulates itself by serving as a first messenger and interacting with its receptor, the calcium-sensing receptor (CASR) on target tissues. The receptor was cloned in 1993 from bovine parathyroid (BoPCAR1) by expression cloning in Xenopus laevis oocytes and is a member of the G protein-coupled receptor super family (2). High calcium levels activate the CASR in the parathyroid cell surface to inhibit PTH secretion, and in the kidney to increase calcium excretion (3). STRUCTURE OF THE CALCIUM-SENSING RECEPTORThe human CASR gene is located on chromosome 3q13.3-21 (4,5) and spans over 50 kb of genomic DNA. It has...

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Section: Neonatal Several Hyperparathyroidismmentioning

confidence: 99%

Section: Inactivating Mutationsmentioning

confidence: 99%

The calcium-sensing receptor and related diseases

D’Souza-Li

2006

Arq Bras Endocrinol Metab

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“…In the past decade, both activating and inactivating mutations of the CASR have been described, resulting in different clinical entities. Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism result from inactivation mutations present in a either heterozygous or homozygous (or compound heterozygous) state (62,63). In addition to hypercalcemia, FHH patients also have a tendency to elevated serum magnesium levels (64).…”

Section: Hypomagnesemia With Secondary Hypocalciuria (Hsh)mentioning

confidence: 99%

Recent Advances in Molecular Genetics of Hereditary Magnesium-Losing Disorders

Konrad¹,

Weber²

2003

Journal of the American Society of Nephrology

111

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Abstract. Recent advances in molecular genetics in hereditary hypomagnesemia substantiated the role of a variety of genes and their encoded proteins in human magnesium transport mechanisms. This knowledge on underlying genetic defects helps to distinguish different clinical subtypes and gives first insight into molecular components involved in magnesium transport. By mutation analysis and functional protein studies, novel pathophysiologic aspects were elucidated. For some of these disorders, transgenic animal models were generated to study genotype-phenotype relations and disease pathology. This review will discuss genetic and clinical aspects of familial disorders associated with magnesium wasting and focuses on the recent progress that has been made in molecular genetics. Besides isolated renal forms of hereditary hypomagnesemia, the following disorders will also be presented: familial hypomagnesemia with hypercalciuria and nephrocalcinosis, hypomagnesemia with secondary hypocalcemia, Ca 2ϩ /Mg 2ϩ -sensing receptor-associated disorders, and disorders associated with renal salt-wasting and hypokalemic metabolic alkalosis, comprising the Gitelman syndrome and the Bartter-like syndromes.

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“…The physiologic importance of this receptor in determining the extracellular calcium concentration has been documented by the characterization of human syndromes resulting from gain or loss-offunction mutations in the CaSR gene. When present in the heterozygous state, loss-of-function mutations cause familial hypocalciuric hypercalcemia (FHH, OMIM 145980), whereas in the homozygous state, these mutations cause neonatal severe hyperparathyroidism (NSHPT, OMIM 239200) (3,4). In contrast, gain-of-function mutations are responsible for a form of autosomal dominant hypocalcemia (ADH, OMIM 601198) (5).…”

mentioning

confidence: 99%

Functional Characterization of a Calcium-Sensing Receptor Mutation in Severe Autosomal Dominant Hypocalcemia with a Bartter-Like Syndrome

Vargas‐Poussou¹,

Huang²,

Hulin³

et al. 2002

Journal of the American Society of Nephrology

313

195

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Abstract. The extracellular Ca 2ϩ -sensing receptor (CaSR) plays an essential role in extracellular Ca 2ϩ homeostasis by regulating the rate of parathyroid hormone (PTH) secretion and the rate of calcium reabsorption by the kidney. Activation of the renal CaSR is thought to inhibit paracellular divalent cation reabsorption in the cortical ascending limb (cTAL) both directly and indirectly via a decrease in NaCl transport. However, in patients with autosomal dominant hypocalcemia (ADH), caused by CaSR gain-of-function mutations, a defect in tubular NaCl reabsorption with renal loss of NaCl has not been described so far. This article describes a patient with ADH due to a gain-of-function mutation in the CaSR, L125P, associated with a Bartter-like syndrome that is characterized by a decrease in distal tubular fractional chloride reabsorption rate and negative NaCl balance with secondary hyperaldosteronism and hypokalemia. The kinetics of activation of the L125P mutant receptor expressed in HEK-293 cells, assessed by measuring CaSR-stimulated changes in intracellular Ca 2ϩ and ERK activity, showed a dramatic reduction in the EC 50 for extracellular Ca 2ϩ compared with the wild-type and a loss-offunction mutant CaSR (I40F). This study describes the first case of ADH associated with a Bartter-like syndrome. It is herein proposed that the L125P mutation of the CaSR, which represents the most potent gain-of-function mutation reported so far, may reduce NaCl reabsorption in the cTAL sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia.

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Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype.

Abstract: Clin. Invest. 1994. 93:1108-1112

Cited by 264 publications

References 20 publications

The calcium-sensing receptor and related diseases

The calcium-sensing receptor and related diseases

Recent Advances in Molecular Genetics of Hereditary Magnesium-Losing Disorders

Functional Characterization of a Calcium-Sensing Receptor Mutation in Severe Autosomal Dominant Hypocalcemia with a Bartter-Like Syndrome

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