The A986S polymorphism of the calcium-sensing receptor (CASR) gene is a significant contributor to inter-individual variability of serum calcium

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.

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Identification of a novel calcium-sensing receptor (CASR) gene mutation in a patient with familial hypocalciuric hypercalcemia

Clinica Chimica Acta ◽

10.1016/j.cca.2019.03.474 ◽

2019 ◽

Vol 493 ◽

pp. S229

Author(s):

M. Ortiz Espejo ◽

R. Batanero Maguregui ◽

C. Montalban Carrasco ◽

L. Ramos Ramos ◽

R. García Sardina ◽

...

Keyword(s):

Gene Mutation ◽

Familial Hypocalciuric Hypercalcemia ◽

Calcium Sensing Receptor ◽

Casr Gene ◽

Calcium Sensing

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A Family of Autosomal Dominant Hypocalcemia with a Positive Correlation between Serum Calcium and Magnesium: Identification of a Novel Gain of Function Mutation (Ser820Phe) in the Calcium-Sensing Receptor

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.87.6.8531 ◽

2002 ◽

Vol 87 (6) ◽

pp. 2681-2687 ◽

Cited By ~ 12

Author(s):

Terumasa Nagase ◽

Takehiko Murakami ◽

Toshihiko Tsukada ◽

Ryuichi Kitamura ◽

Noriko Chikatsu ◽

...

Keyword(s):

Serum Calcium ◽

Autosomal Dominant ◽

Calcium Sensing Receptor ◽

Gain Of Function ◽

Positive Correlation ◽

Calcium Sensing ◽

Calcium And Magnesium ◽

Autosomal Dominant Hypocalcemia

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Hipocalcemia Crónica por Anticorpos Anti-Recetor do Cálcio

Acta Médica Portuguesa ◽

10.20344/amp.4408 ◽

2014 ◽

Vol 27 (3) ◽

pp. 399

Author(s):

Pedro Marques ◽

Rita Santos ◽

Branca Cavaco ◽

Valeriano Leite

Keyword(s):

Parathyroid Hormone ◽

Genetic Disorder ◽

Neck Surgery ◽

Urinary Calcium ◽

Clinical Report ◽

Calcium Sensing Receptor ◽

Casr Gene ◽

Calcium Sensing ◽

Calcium Phosphorus ◽

Receptor Antibodies

Introduction: Hypoparathyroidism is an entity associated with hypocalcemia, more frequently a consequence of neck surgery. An autoimmune etiology is rare and its diagnosis difficult to establish. Clinical report: 52 year-old woman, with irrelevant past medical history and no significant familial conditions, referred because of hypocalcemia and basal ganglia calcifications, detected in the course of investigation of myalgias. Besides hypocalcemia (4.6 mg/ dL), hyperphosphatemia (8.7 mg/dL), undetectable parathyroid hormone and low urinary calcium, phosphorus and magnesium were present. Molecular analysis of CaSR gene excluded germinal mutations. Anti-calcium sensing receptor antibodies (anti-CaSR) were present. The patient is asymptomatic and normocalcemic under treatment with calcium and vitamin D. Discussion: Although rare, hypocalcemia due to anti-CaSR hypoparathyroidism must be considered in the absence of previous neck surgery, hypocalcemic drugs, familial history or phenotype suggesting a genetic disorder. Low or undetectable parathyroid hormone excludes pseudohypoparathyroidism and anti-CaSR positivity establishes the diagnosis. Keywords: Hypocalcemia; Hypoparathyroidism; Autoantibodies; Receptors, Calcium-Sensing.

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Neonatal Severe Hyperparathyroidism due to Compound Heterozygous Mutation of Calcium Sensing Receptor (CaSR) Gene Presenting as Encephalopathy

The Indian Journal of Pediatrics ◽

10.1007/s12098-014-1442-3 ◽

2014 ◽

Vol 81 (11) ◽

pp. 1228-1229 ◽

Cited By ~ 3

Author(s):

Abhishek Kulkarni ◽

Mahesh Mohite ◽

Ramaa Vijaykumar ◽

Prasanna Bansode ◽

Sachin Murade ◽

...

Keyword(s):

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Calcium Sensing Receptor ◽

Casr Gene ◽

Calcium Sensing

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Association of common variants in the calcium-sensing receptor gene with serum calcium levels in East Asians

Journal of Human Genetics ◽

10.1038/jhg.2015.46 ◽

2015 ◽

Vol 60 (8) ◽

pp. 407-412 ◽

Cited By ~ 9

Author(s):

Nadimuthu Vinayagamoorthy ◽

Seon-Hee Yim ◽

Seung-Hyun Jung ◽

Sung-Won Park ◽

Young Jin Kim ◽

...

Keyword(s):

Serum Calcium ◽

Receptor Gene ◽

Common Variants ◽

Calcium Sensing Receptor ◽

East Asians ◽

Calcium Sensing ◽

Calcium Sensing Receptor Gene

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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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-0123 ◽

2007 ◽

Vol 92 (7) ◽

pp. 2616-2623 ◽

Cited By ~ 44

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>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.

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