The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families

Yh, Chou; Em, Brown; Levi, Tatjana; Crowe, G; Ab, Atkinson; Hj, Arnqvist; Toss, Göran; Ge, Fuleihan; Jg, Seidman; Seidman, C E

doi:10.1038/ng0792-295

Cited by 147 publications

(48 citation statements)

References 21 publications

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“…In 1992, Chou et al showed linkage of the disease gene for FBHH to the long arm of chromosome 3 (27). Subsequently, additional workers confirmed this finding but also demonstrated that a similar phenotype was linked to the short arm of chromosome 19 (28) in one family and to a locus on neither chromosome 3 nor 19 in another (29).…”

Section: Introductionsupporting

confidence: 53%

In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia.

Bai¹,

Pearce²,

Kifor³

et al. 1997

J. Clin. Invest.

189

130

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We characterized the in vivo, cellular and molecular pathophysiology of a case of neonatal hyperparathyroidism (NHPT) resulting from a de novo, heterozygous missense mutation in the gene for the extracellular Ca 2 ϩ ( )-sensing receptor (CaR). The female neonate presented with moderately severe hypercalcemia, markedly undermineralized bones, and multiple metaphyseal fractures. Subtotal parathyroidectomy was performed at 6 wk; hypercalcemia recurred rapidly but the bone disease improved gradually with reversion to an asymptomatic state resembling familial benign hypocalciuric hypercalcemia (FBHH). Dispersed parathyroid cells from the resected tissue showed a set-point (the level of half maximally inhibiting PTH secretion) substantially higher than for normal human parathyroid cells ( ‫ف‬ 1.8 vs.

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Section: Introductionsupporting

confidence: 53%

In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia.

Bai¹,

Pearce²,

Kifor³

et al. 1997

J. Clin. Invest.

189

130

View full text Add to dashboard Cite

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“…In heterozygotes, inactivating CaR mutations cause familial benign hypocalciuric hypercalcemia, and in homozygotes, severe neonatal primary hyperparathyroidism (8,9). In contrast, activating CaR mutations result in autosomal dominant hypocalcemia (10,11).…”

Section: Ntracellular Camentioning

confidence: 99%

Treatment of Secondary Hyperparathyroidism in CKD Patients with Cinacalcet and/or Vitamin D Derivatives

Drüeke¹,

Ritz²

2009

Clinical Journal of the American Society of Nephrology

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The discovery of the calcium-sensing receptor (CaR) 15 yr ago was rapidly followed by the development of drugs modulating its activity, the so-called calcimimetics (increasing the CaR signal) and calcilytics (decreasing the CaR signal). The indication for calcimimetics is treatment of primary and secondary hyperparathyroidism, whereas calcilytics have potential for treatment of osteoporosis. A large number of clinical studies has shown that cinacalcet, the only presently available calcimimetic, effectively reduces serum parathyroid hormone in dialysis patients with secondary hyperparathyroidism. In contrast to the effect of active vitamin D derivatives, it simultaneously decreases serum calcium and phosphorus. Experimental studies showed a concomitant decrease in parathyroid hyperplasia. In the treatment of secondary hyperparathyroidism of dialysis patients, important questions remain unresolved, for example, whether there are reasons to prefer calcimimetics to active vitamin D derivatives and whether combined administration offers advantages compared with calcimimetics or active vitamin D given in isolation. For lowering parathyroid hormone, available evidence from recent studies suggests that combination therapy should be preferred to single drug treatment because of less side-effects and greater efficacy in controlling parathyroid overfunction. Future randomized controlled trial must answer whether calcimimetics impact on cardiovascular events or survival and whether in this respect there are differences between vitamin D sterols and calcimimetics.

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“…The CASR was also demonstrated in human insulinoma primary cultures, causing released insulin upon [Ca 2+ o ] stimulation (59), in hepatocytes stimulating bile flow (60) and in antral gastric cells stimulating gastrin secretion (61). (69) and later fluorescence in situ hybridization analysis identified the position of the gene as 3q 13.3-21 (4). Cloning of the CASR was followed by reports of inactivating mutations in this gene in FHH families (70,71).…”

Section: Role Of the Calcium-sensing Receptor In Other Tissuesmentioning

confidence: 99%

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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The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families

Cited by 147 publications

References 21 publications

In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia.

In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia.

Treatment of Secondary Hyperparathyroidism in CKD Patients with Cinacalcet and/or Vitamin D Derivatives

The calcium-sensing receptor and related diseases

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