scholarly journals Identification of a Second Kindred with Familial Hypocalciuric Hypercalcemia Type 3 (FHH3) Narrows Localization to a <3.5 Megabase Pair Region on Chromosome 19q13.3

2010 ◽  
Vol 95 (4) ◽  
pp. 1947-1954 ◽  
Author(s):  
M. Andrew Nesbit ◽  
Fadil M. Hannan ◽  
Una Graham ◽  
Michael P. Whyte ◽  
Patrick J. Morrison ◽  
...  
Keyword(s):  
Elevated Serum ◽  
Urinary Calcium ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Coding Region ◽  
Calcium Sensing Receptor ◽  
Single Nucleotide ◽  
Polymorphic Loci ◽  
Calcium Sensing ◽  
Serum Pth ◽  
Type 3

Abstract Context: Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogenous disorder that consists of three defined types, FHH1, FHH2, and FHH3 whose chromosomal locations are 3q21.1, 19p, and 19q13, respectively. FHH1, caused by mutations of the calcium-sensing receptor (CASR), occurs in more than 65% of patients, whereas the abnormalities underlying FHH2 and FHH3, which have each been described in single North American kindreds, are unknown. Objective: The aim of this study was to determine the basis of FHH in a proband, who did not have CASR mutations, and her kindred. Patients and Methods: The proband was a 43-yr-old woman who presented with a corrected serum calcium of 2.74 mmol/liter (normal = 2.15–2.55 mmol/liter), a serum PTH of 47 pg/ml (normal = 10–65 pg/ml), and a urinary calcium clearance:creatinine clearance of 0.006. She did not have a CASR mutation within the coding region and splice sites, and 24 members from three generations of her kindred were ascertained and investigated for serum abnormalities and cosegregation with polymorphic loci from chromosomes 3q21.1 and 19q13 using leukocyte DNA. Results: Sixteen members were hypercalcemic with normal or elevated serum PTH concentrations and mild hypophosphatemia, features consistent with FHH3. Use of microsatellite and single nucleotide polymorphic loci from chromosome 19q13.3 demonstrated cosegregation with FHH in the kindred, with a peak LOD score = 5.98 at 0% recombination with D19S412. Analysis of recombinants mapped FHH to a 3.46-Mbp interval flanked centromerically by single nucleotide polymorphism rs1990932 and telomerically by D19S604. Conclusions: FHH3 may explain the calcium homeostasis disorder in those FHH patients who do not have CASR mutations.

scholarly journals Identification and Functional Characterization of a Novel Mutation in the Calcium-Sensing Receptor Gene in Familial Hypocalciuric Hypercalcemia: Modulation of Clinical Severity by Vitamin D Status

2007 ◽  
Vol 92 (7) ◽  
pp. 2616-2623 ◽  
Author(s):  
Katerina Zajickova ◽  
Jana Vrbikova ◽  
Lucie Canaff ◽  
Peter D. Pawelek ◽  
David Goltzman ◽  
...  
Keyword(s):  
Vitamin D ◽  
Gene Mutation ◽  
Clinical Severity ◽  
Vitamin D Status ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Calcium Sensing Receptor ◽  
Benign Condition ◽  
Casr Gene ◽  
Calcium Sensing ◽  
Serum Pth

Abstract Context: Familial hypocalciuric hypercalcemia (FHH) is a benign condition associated with heterogeneous inactivating mutations in the calcium-sensing receptor (CASR) gene. Objective: The objective of the study was to identify and characterize a CASR mutation in a moderately hypercalcemic, hyperparathyroid individual and his family and assess the influence of vitamin D status on the clinical expression of the defect. Subjects: We studied a kindred with FHH, in which the proband (a 34-yr-old male) was initially diagnosed with primary hyperparathyroidism due to frankly elevated serum PTH levels. Methods: CASR gene mutation analysis was performed on genomic DNA of the proband and family members. The mutant CASR was functionally characterized by transient transfection studies in kidney cells in vitro. Results: A novel heterozygous mutation (F180C, TTC&gt;TGC) in exon 4 of the CASR gene was identified. Although the mutant receptor was expressed normally at the cell surface, it was unresponsive with respect to intracellular signaling (MAPK activation) to increases in extracellular calcium concentrations. The baby daughter of the proband presented with neonatal hyperparathyroidism with markedly elevated PTH. Vitamin D supplementation of both the proband and the baby resulted in reduction of serum PTH levels to the normal range. The serum calcium level remained at a constant and moderately elevated level. Conclusion: The identification of a novel CASR gene mutation established the basis of the hypercalcemia in the kindred. Concomitant vitamin D deficiency modulates the severity of the presentation of FHH.

scholarly journals R990G polymorphism of the calcium-sensing receptor and renal calcium excretion in patients with primary hyperparathyroidism

2006 ◽  
Vol 155 (5) ◽  
pp. 687-692 ◽  
Author(s):  
S Corbetta ◽  
C Eller-Vainicher ◽  
M Filopanti ◽  
P Saeli ◽  
G Vezzoli ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
Urinary Calcium ◽  
Calcium Excretion ◽  
Calcium Sensing Receptor ◽  
Gene Encoding ◽  
Calcium Sensing ◽  
Standard Procedures ◽  
Renal Complication ◽  
Serum Pth ◽  
Bone Complications

Context: Primary hyperparathyroidism (PHPT) shows a great variability in clinical course and severity. Data concerning the association between polymorphic variants of the gene encoding the calcium-sensing receptor (CaSR) and clinical characteristics of PHPT are not conclusive. Objective: To evaluate the frequency of three polymorphisms; A986S, R990G, and Q1011E of CaSR in patients with PHPT and to correlate the genotypes with clinical and biochemical parameters. Patients and methods: The study included 94 consecutive unrelated patients referred to our Departments for PHPT diagnosis and management between 2000 and 2005 and 137 age and sex-matched healthy subjects. Patients and controls were genotyped according to standard procedures. Due to the rarity of 990G allele, homozygous and heterozygous subjects were grouped in R/G+G/G set. All PHPT patients were studied for calcium metabolism parameters and renal and bone complications. Results: The proportion of CaSRvariants was similar in PHPT patients and controls. In PHPT patients, only R990G polymorphism was associated with disease parameters; in comparison with R/R, R/G+G/G patients showed lower mean serum parathyroid hormone (PTH) and phosphate levels (139.9 ± 62.2 vs 199.9 ± 136.3 pg/ml, P < 0.05 and 0.69 ± 0.12 vs 0.81 ± 0.18 mmol/l, P = 0.031 respectively), higher mean 24-h urine calcium concentration and calcium excretion (9.05 ± 2.05 vs 6.77 ± 4.31 mmol/24 h, P = 0.012 and 67 ± 20 vs 51 ± 26 μmol/l GF, P = 0.039), and increased prevalence of nephrolithiasis (90.0 vs 44.2%, P = 0.007). Conclusions: The study showed that patients with PHPT, bearing the 990G allele, had lower serum PTH levels and higher urinary calcium excretion in comparison with the other genotype, suggesting an increased sensitivityof the variant receptor to extracellular calcium. Since this variant was associated with increased occurrence of nephrolithiasis, analysis of this polymorphism might help to predict renal complication of the disease.

scholarly journals Type 1 Familial Hypocalciuric Hypercalcemia Caused by p.M74L Variant in the Calcium Sensing Receptor (CASR) Gene

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A230-A230
Author(s):  
McAnto Antony ◽  
Alvin Maliakal ◽  
Jameson Burdette ◽  
Vipin Verma ◽  
Ravi Kant
Keyword(s):  
Chromosome 3 ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Calcium Sensing Receptor ◽  
Blood Calcium ◽  
Casr Gene ◽  
Calcium Sensing ◽  
Patient Reported ◽  
History Of ◽  
Serum Pth ◽  
Inactivating Mutations

Abstract Background: Familial hypocalciuric hypercalcemia (FHH) is a rare cause of hypercalcemia caused by inactivating mutations in specific regions of chromosome 3 and 19. Most cases are due to inactivating mutations in the Calcium sensing receptor (CASR) which is encoded by the gene located on the long arm of chromosome 3 (3q 21.1). FHH is characterized by hypercalcemia, an inappropriately normal to elevated serum PTH level, hypocalciuria, and a family history of hypercalcemia. Several mutations in the CASR gene have been described in literature. However, the p.M74L variant in the CASR gene has an extremely low frequency of occurrence in population databases such as the genome aggregation database (gnomAD)1. Clinical Case: A 67 years old woman with a past medical history of hypertension, dyslipidemia, type 2 diabetes mellitus, and chronic kidney disease presented for an evaluation of a long standing history of hypercalcemia. Patient reported non-specific symptoms including chronic fatigue and arthralgias. She denied a history of renal stone or chronic use of lithium. She distinctly recalled that her mother and maternal grandmother had high blood calcium levels. Review of old records showed an elevated corrected calcium level of 11.3 mg/dl, which was elevated since at least October 2013 (no medical records prior to October 2013 were available) which persisted to-date. Patient underwent work-up which revealed a high corrected serum calcium of 10.4 (8.6–10.0mg/dl), high serum PTH of 101 (15–65 pg/ml), an extremely low 24hr urine calcium of &lt;9.2 (100–300 mg/24hr) with corresponding urine volume of 1150 cc and urine creatinine of 1392 (740–1570 mg/24hr), low 25-OH vitamin D of 20.6 (30–100 ng/ml), and a low eGFR of 47 ml/m/1.73. SPECT parathyroid gland was negative. FHH was suspected and subsequent CASR gene analysis panel showed a heterogenous DNA sequence change at nucleotide position c.220 in exon 3 of the CASR gene (c.220A&gt;C). This nucleotide change results in an amino acid change from methionine (M) to leucine (L) at position 74 in the CASR protein (p.M74L). Conclusion: We report a case of a p.M74L variant in the CASR gene which is an extremely uncommon mutation in the CASR gene1. Our case supports the current limited evidence that p.M74L variant in the CASR gene can cause FHH. References: 1) Genome Aggregation Database: https://gnomad.broadinstitute.org/

scholarly journals A Novel Variant in the Calcium-Sensing Receptor Associated with Familial Hypocalciuric Hypercalcemia and Low-to-Normal PTH

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Sachin K. Majumdar ◽  
Tess Jacob ◽  
Allen Bale ◽  
Allison Bailey ◽  
Jeffrey Kwon ◽  
...  
Keyword(s):  
Serum Calcium ◽  
Urinary Calcium ◽  
Urinary Calcium Excretion ◽  
Calcium Excretion ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Calcium Sensing Receptor ◽  
Benign Condition ◽  
Casr Gene ◽  
Calcium Sensing ◽  
Novel Variant

Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by mild elevations in serum calcium and relatively low urinary calcium excretion. It results from an elevated set point in serum calcium arising from variants in the calcium-sensing receptor (CaSR) gene but also AP2S1 and GNA11 genes, which encode for adaptor-related protein complex 2 and G11 proteins, respectively. The manifestations of FHH can vary and sometimes overlap with primary hyperparathyroidism making the diagnosis challenging. Case Presentations. We report a mother and daughter with a novel heterozygous variant in the CaSR gene resulting in a serine to leucine substitution at position 147 (S147L) of the CaSR. Both patients had mild hypercalcemia, relatively low urinary calcium excretion, elevated calcitriol, and low-to-normal intact PTH. The proband (daughter) presented with symptoms associated with hypercalcemia and was incidentally found to have a bony lesion suspicious for osteitis fibrosa cystica, and she was also diagnosed with sarcoidosis. Subtotal parathyroidectomy revealed normal-weight parathyroid glands comprised of 50–80% parathyroid epithelial cells, which has been documented as within the spectrum of normal. Her mother had no symptoms, and no intervention was pursued. Conclusion. We report a novel variant in the CaSR associated with FHH in two patients with similar biochemical features yet differing clinical manifestations. While the relationship of the bony findings and parathyroid histology with this variant remains unclear, these cases enrich our knowledge of CaSR physiology and provide further examples of how varied the manifestations of FHH can be.

scholarly journals Molecular and clinical insights from studies of calcium-sensing receptor mutations

2019 ◽  
Vol 63 (2) ◽  
pp. R1-R16 ◽  
Author(s):  
Caroline M Gorvin
Keyword(s):  
G Protein ◽  
Structural Integrity ◽  
Elevated Serum ◽  
Failure To Thrive ◽  
Receptor Activation ◽  
Urinary Calcium ◽  
Signalling Pathways ◽  
Calcium Excretion ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Twenty-five years have elapsed since the calcium-sensing receptor (CaSR) was first identified in bovine parathyroid and the receptor is now recognized as a fundamental contributor to extracellular Ca2+ (Ca2+ e) homeostasis, regulating parathyroid hormone release and urinary calcium excretion. The CaSR is a class C G-protein-coupled receptor (GPCR) that is functionally active as a homodimer and couples to multiple G-protein subtypes to activate intracellular signalling pathways. The importance of the CaSR in the regulation of Ca2+ e has been highlighted by the identification of >400 different germline loss- and gain-of-function CaSR mutations that give rise to disorders of Ca2+ e homeostasis. CaSR-inactivating mutations cause neonatal severe hyperparathyroidism, characterised by marked hypercalcaemia, skeletal demineralisation and failure to thrive in early infancy; and familial hypocalciuric hypercalcaemia, an often asymptomatic disorder associated with mild-moderately elevated serum calcium concentrations. Activating mutations are associated with autosomal dominant hypocalcaemia, which is occasionally associated with a Bartter’s-like phenotype. Recent elucidation of the CaSR extracellular domain structure enabled the locations of CaSR mutations to be mapped and has revealed clustering in locations important for structural integrity, receptor dimerisation and ligand binding. Moreover, the study of disease-causing mutations has demonstrated that CaSR signals in a biased manner and have revealed specific residues important for receptor activation. This review presents the current understanding of the genetic landscape of CaSR mutations by summarising findings from clinical and functional studies of disease-associated mutations. It concludes with reflections on how recently uncovered signalling pathways may expand the understanding of calcium homeostasis disorders.

scholarly journals Identification and Functional Characterization of a Calcium-Sensing Receptor Mutation in an Infant with Familial Hypocalciuric Hypercalcemia

2016 ◽  
Vol 8 (3) ◽  
pp. 341-346 ◽  
Author(s):  
Anna Papadopoulou ◽  
Evangelia Gole ◽  
Katerina Melachroinou ◽  
Christos Meristoudis ◽  
Tania Siahanidou ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing
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