A Familial Syndrome of Hypocalcemia with Hypercalciuria Due to Mutations in the Calcium-Sensing Receptor

Pearce, Simon H. S.; Williamson, Catherine; Kifor, Olga; Bai, Ming; Coulthard, Malcolm; Davies, M.; Lewis‐Barned, Nick; McCredie, David A.; Powell, Harley R.; Kendall‐Taylor, P.; Brown, Edward M.; Thakker, Rajesh V.

doi:10.1056/nejm199610103351505

Cited by 569 publications

(471 citation statements)

References 33 publications

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“…The calcium-sensing receptor can also activate phospholipase A2 to produce arachidonic acid, the metabolites of which, including 20-HETE, inhibit NKCC2 and ROMK. In support of this mechanism, Pearce et al have found six kindreds with an autosomal dominant inheritance of hypocalcemia and hypercalciuria who proved to have activating mutations in the calcium-sensing receptor (111,112). Vezzoli et al (113) examined four single-nucleotide polymorphisms (SNP) in exon 7 of the calcium-sensing receptor and found one SNP associated with a 13-fold higher risk of hypercalciuria.…”

Section: Dent Disease (X-linked Recessive Nephrolithiasis) Dent and mentioning

confidence: 99%

Molecular Mechanisms of Primary Hypercalciuria

Frick¹,

Bushinsky²

2003

Journal of the American Society of Nephrology

127

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Section: Dent Disease (X-linked Recessive Nephrolithiasis) Dent and mentioning

confidence: 99%

Molecular Mechanisms of Primary Hypercalciuria

Frick¹,

Bushinsky²

2003

Journal of the American Society of Nephrology

127

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“…(1–3) The CaSR is a guanine‐nucleotide binding protein (G‐protein)‐coupled receptor (GPCR) that plays a pivotal role in Ca 2+ o homeostasis by transducing increases in the prevailing Ca 2+ o concentration into multiple signaling cascades that include G q/11 ‐protein–mediated activation of phospholipase C (PLC), which in the parathyroid glands and kidneys induces rapid increases in intracellular calcium (Ca 2+ i ) that lead to decreased parathyroid hormone (PTH) secretion and increased urinary calcium excretion, respectively 2, 4, 5. ADH is a genetically heterogeneous disorder most commonly caused by germline gain‐of‐function mutations of the CaSR, which is encoded by the CASR gene on chromosome 3q21.1, and this is referred to as ADH type 1 (ADH1; OMIM #601198) 1, 2, 5. However, some ADH patients and families have recently been shown to harbor germline mutations of G‐protein subunit‐α11 (Gα 11 ), which is encoded by the GNA11 gene (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…ADH1 patients have calcitropic phenotypes, such as hypocalcemia with inappropriately low or normal PTH concentrations and a relative hypercalciuria that is characterized by urinary calcium to creatinine ratios that are within or above the reference range,1, 8, 9 and mice with a gain‐of‐function CaSR mutation, that are representative of ADH1, have been reported to also have non‐calcitropic phenotypes such as cataracts 10. Although these features are similar to hypoparathyroidism, ADH1 is considered to represent a distinct disease entity from hypoparathyroidism, because affected individuals generally have PTH concentrations that are detectable and within the reference range 1, 8. Furthermore, ADH1 patients may also develop a Bartter‐like syndrome characterized by hypokalemic alkalosis, renal salt wasting, and hyperreninemic hyperaldosteronism,11, 12 and the use of active vitamin D metabolites to treat symptomatic ADH1 patients may result in the development of marked hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal impairment 1, 9.…”

Section: Introductionmentioning

confidence: 99%

Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

Piret

Gorvin

Pagnamenta

et al. 2016

Journal of Bone and Mineral Research

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Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormone concentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being caused by germline gain‐of‐function mutations of the G‐protein coupled calcium‐sensing receptor (CaSR), and ADH2 caused by germline gain‐of‐function mutations of G‐protein subunit α‐11 (Gα11). To date Gα11 mutations causing ADH2 have been reported in only five probands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are not known to be associated, for causative mutations by whole‐exome sequencing in two individuals with hypoparathyroidism, of whom one also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340Met Gα11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Three‐dimensional modeling revealed the Val340Met mutation to likely alter the conformation of the C‐terminal α5 helix, which may affect G‐protein coupled receptor binding and G‐protein activation. In vitro functional expression of wild‐type (Val340) and mutant (Met340) Gα11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses following stimulation with extracellular calcium, of the mutant Met340 Gα11 led to a leftward shift of the concentration‐response curve with a significantly (p < 0.0001) reduced mean half‐maximal concentration (EC50) value of 2.44 mM (95% CI, 2.31 to 2.77 mM) when compared to the wild‐type EC50 of 3.14 mM (95% CI, 3.03 to 3.26 mM), consistent with a gain‐of‐function mutation. A novel His403Gln variant in transforming growth factor, beta‐induced (TGFBI), that may be causing keratoconus was also identified, indicating likely digenic inheritance of keratoconus and ADH2 in this family. In conclusion, our identification of a novel germline gain‐of‐function Gα11 mutation, Val340Met, causing ADH2 demonstrates the importance of the Gα11 C‐terminal region for G‐protein function and CaSR signal transduction. © 2016 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

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“…Genetic forms of HP are rare and usually associated with mutations in four genes: calcium‐sensing receptor ( CASR ) (Bai et al 1996; Pearce et al 1996; Watanabe et al 1998), glial cells missing homolog 2 ( GCM2 ) (Ding et al 2001), guanine nucleotide‐binding protein alpha‐11 ( GNA11 ) (Mannstadt et al 2013), and PTH itself (Arnold et al 1990; Parkinson & Thakker 1992; Sunthornthepvarakul et al 1999). …”

mentioning

confidence: 99%

Pseudohypoparathyroidism type I‐b with neurological involvement is associated with a homozygous PTH1R mutation

Guerreiro

Brás

Batista

et al. 2016

Genes Brain and Behavior

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Pseudohypoparathyroidism type 1b (PHP1b) is characterized by hypocalcemia, hyperphosphatemia, increased levels of circulating parathyroid hormone (PTH), and no skeletal or developmental abnormalities. The goal of this study was to perform a full characterization of a familial case of PHP1b with neurological involvement and to identify the genetic cause of disease. The initial laboratory profile of the proband showed severe hypocalcemia, hyperphosphatemia and normal levels of PTH, which was considered to be compatible with primary hypoparathyroidism. With disease progression the patient developed cognitive disturbance, PTH levels were found to be slightly elevated and a picture of PTH resistance syndrome seemed more probable. The diagnosis of PHP1b was established after the study of family members and blunted urinary cAMP results were obtained in a PTH stimulation test. Integration of whole genome genotyping and exome sequencing data supported this diagnosis by revealing a novel homozygous missense mutation in PTH1R (p.Arg186His) completely segregating with the disease. Here, we demonstrate segregation of a novel mutation in PTH1R with a phenotype of PHP1b presenting with neurological symptoms, but no bone defects. This case represents the extreme end of the spectrum of cognitive impairment in PTH dysfunction and defines a possible novel form of PHP1b resulting from the impaired interaction between PTH and PTH1R.

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A Familial Syndrome of Hypocalcemia with Hypercalciuria Due to Mutations in the Calcium-Sensing Receptor

Abstract: Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.

Cited by 569 publications

References 33 publications

Molecular Mechanisms of Primary Hypercalciuria

Molecular Mechanisms of Primary Hypercalciuria

Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

Pseudohypoparathyroidism type I‐b with neurological involvement is associated with a homozygous PTH1R mutation

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