Autosomal dominant hypocalcaemia caused by a Ca2+-sensing receptor gene mutation

Pollak, Martin R.; Brown, Edward M.; Estep, Herschel L.; McLaine, Peter N.; Kifor, Olga; Park, Ji; Hebert, Steven C.; Seidman, Christine E.

doi:10.1038/ng1194-303

Cited by 548 publications

(305 citation statements)

References 16 publications

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“…E xtracellular calcium ([Ca 2þ ] e ) and the activated form of vitamin D [1,25(OH) 2 D] play important roles in modulating systemic calcium homeostasis. [Ca 2þ ] e activates a cation-sensing G protein-coupled receptor (CaSR) to modulate the concentrations of circulating parathyroid hormone (PTH) and to regulate renal calcium reabsorption.…”

Section: Introductionmentioning

confidence: 99%

“…(1) Gain-of-function mutations in the CASR gene in humans cause autosomal dominant hypocalcemia, a condition of mild to moderate hypocalcemia associated with suppression of PTH secretion that can be accompanied by hypercalciuria. (2) Loss-of-function mutations in the CASR gene cause familial benign hypocalciuric hypercalcemia in heterozygotes and neonatal severe hyperparathyroidism in homozygotes, both associated with increased PTH secretion and diminished renal calcium excretion but of differing severities. (3) Targeted deletion of the Casr gene in mice produced a phenocopy of the human condition resulting from inactivating CASR mutations.…”

Section: Introductionmentioning

confidence: 99%

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The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

Richard

Huo

Samadfam

et al. 2010

Journal of Bone and Mineral Research

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We examined parathyroid and skeletal function in 3-month-old mice expressing the null mutation for 25-hydroxyvitamin D-1a-hydroxylase [1a(OH)ase À/À ] and in mice expressing the null mutation for both the 1a(OH)ase and the calcium-sensing receptor [Casr À/À 1a(OH)ase À/À ] genes. On a normal diet, all mice were hypocalcemic, with markedly increased parathyroid hormone (PTH), increased trabecular bone volume, increased osteoblast activity, poorly mineralized bone, enlarged and distorted cartilaginous growth plates, and marked growth retardation, especially in the compound mutants. Osteoclast numbers were reduced in the Casr À/À 1a(OH)ase À/À mice. On a high-lactose, high-calcium, high-phosphorus ''rescue'' diet, serum calcium and PTH were normal in the 1a(OH)ase À/À mice but increased in the Casr À/À 1a(OH)ase À/À mice with reduced serum phosphorus. Growth plate architecture and mineralization were improved in both mutants, but linear growth of the double mutants remained abnormal. Mineralization of bone improved in all mice, but osteoblast activity and trabecular bone volume remained elevated in the Casr À/À 1a(OH)ase À/À mice. These studies support a role for calcium-stimulated maturation of the cartilaginous growth plate and mineralization of the growth plate and bone and calcium-stimulated CaSR-mediated effects on bone resorption. PTH-mediated bone resorption may require calcium-stimulated CaSR-mediated enhancement of osteoclastic activity. ß

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

Richard

Huo

Samadfam

et al. 2010

Journal of Bone and Mineral Research

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“…within the lower half of the normal range or frankly subnormal. 73 Affected individuals often exhibit relative or absolute hypercalciuria, with normal or frankly elevated urinary calcium excretion, respectively, in spite of their low serum calcium concentration. Some, but not all, studies have shown that renal calcium excretion in ADH is higher than that in typical hypoparathyroidism.…”

Section: Clinical and Genetic Features Of Autosomal-dominant Hypoparamentioning

confidence: 99%

Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations

Egbuna

Brown

2008

Best Practice & Research Clinical Rheumatology

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191

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The extracellular calcium (Ca 2+ o )-sensing receptor (CaSR) enables the parathyroid glands and other CaSR-expressing cells involved in calcium homeostasis, such as the kidney and bone, to sense alterations in the level of Ca 2+ o and to respond with changes in function that are directed at normalizing the blood calcium concentration. Several disorders of Ca 2+ o sensing arise from inherited or acquired abnormalities that 'reset' the serum calcium concentration upwards or downwards. Heterozygous inactivating mutations of the CaSR produce a benign form of hypercalcaemia, termed 'familial hypocalciuric hypercalcaemia', while homozygous mutations produce a much more severe hypercalcaemic disorder resulting from marked hyperparathyroidism, called 'neonatal severe hyperparathyroidism'. Activating mutations cause a hypocalcaemic syndrome of varying severity, termed 'autosomal-dominant hypocalcaemia or hypoparathyroidism' as well as Bartter's syndrome type V. Calcimimetic CaSR activators and calcilytic CaSR antagonists have also been developed with potential for use in the treatment of these disorders. Keywordsseven transmembrane receptor; mutations; polymorphisms; calcium-sensing receptor; calcium homeostasis; calcimimetic; calcilytic; familial hypocalciuric hypercalcaemia; autosomal-dominant hypoparathyroidism; acquired hypoparathyroidism; osteoporosis; hyperparathyroidism; Bartter's syndromeThe calcium-sensing receptor (CaSR) plays key roles in the maintenance of a narrow range (1.1-1.3 mM) of the extracellular ionized calcium concentration (Ca 2+ o ), primarily by modulating the function of chief cells of the parathyroid gland. Here it regulates the synthesis and secretion of parathyroid hormone (PTH) as well as parathyroid cellular proliferation, inhibiting all three when Ca 2+ o is high and stimulating them when Ca 2+ o is low. 1 Both very high and very low levels of Ca 2+ o can lead to serious clinical sequellae and, in some instances,

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“…Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by elevated PTH levels (Khosla et al 1993). Others involve inactivating mutations in the CaSR gene, resulting in familial hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism (NSHPT; Pollak et al 1993), whereas autosomal dominant hypocalcemia (ADH) is caused by activating mutations (Pollak et al 1994). From the clinical symptoms of these PTH-related disorders, like hypoor hypercalciuria and renal stone formation, it is clear that also renal Ca 2+ handling is affected.…”

Section: Pth-related Disordersmentioning

confidence: 99%

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

Abel

Hoenderop

Bindels

2005

Naunyn-Schmiedeberg's Arch Pharmacol

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The epithelial Ca 2+ channels TRPV5 and TRPV6 represent a new family of Ca 2+ channels that belongs to the superfamily of transient receptor potential channels. TRPV5 and TRPV6 constitute the apical Ca 2+ entry mechanism in active Ca 2+ transport in kidney and intestine. The central role of TRPV5 and TRPV6 in active Ca 2+ (re)absorption makes it a prime target for regulation to maintain Ca 2+ balance. This review covers the hormonal regulation, interaction with accessory proteins and (patho)physiological implications of these epithelial Ca 2+ channels.

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Autosomal dominant hypocalcaemia caused by a Ca2+-sensing receptor gene mutation

Cited by 548 publications

References 16 publications

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

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