Novel mutations associated with inherited human calcium-sensing receptor disorders: A clinical genetic study

in European Journal of Endocrinology
Correspondence should be addressed to L Castaño; Email:

*(A García-Castaño and L Madariaga contributed equally to this work)

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Molecular diagnosis is a useful diagnostic tool in calcium metabolism disorders. The calcium-sensing receptor (CaSR) is known to play a central role in the regulation of extracellular calcium homeostasis. We performed clinical, biochemical and genetic characterization of sequence anomalies in this receptor in a cohort of 130 individuals from 82 families with suspected alterations in the CASR gene, one of the largest series described.


The CASR gene was screened for mutations by polymerase chain reaction followed by direct Sanger sequencing.


Presumed CaSR-inactivating mutations were found in 65 patients from 26 families. These patients had hypercalcemia (median: 11.3 mg/dL) but normal or abnormally high parathyroid hormone (PTH) levels (median: 52 pg/mL). On the other hand, presumed CaSR-activating mutations were detected in 17 patients from eight families. These patients had a median serum calcium level of 7.4 mg/dL and hypoparathyroidism (median: PTH 13 pg/mL). Further, common polymorphisms previously associated with high blood ionized calcium levels were found in 27 patients (median calcium: 10.6 mg/dL; median PTH: 65 pg/mL) with no other alterations in CASR. Overall, we found 30 different mutations, of which, 14 have not been previously reported (p.Ala26Ser, p.Cys60Arg, p.Lys119Ile, p.Leu123Met, p.Glu133Val, p.Gly222Glu, p.Phe351Ile, p.Cys542Tyr, p.Cys546Gly, p.Cys677Tyr, p.Ile816Val, p.Ala887Asp, p.Glu934*, p.Pro935_Gln945dup).


Patients with CASR mutations may not fit the classic clinical pictures of hypercalcemia with hypocalciuria or hypocalcemia with hypercalciuria. Molecular studies are important for confirming the diagnosis and distinguishing it from other entities. Our genetic analysis confirmed CaSR disorders in 82 patients in the study cohort.

Downloadable materials

  • Table 1. Clinical characteristics and laboratory findings observed in patients with inactivating mutation (65 patients), activating mutation (17 patients), polymorphisms (27 patients) in the CASR gene, and patients without alterations in the CASR gene (21 patients) (expressed as Median [IQR]). N, Patients with available data; NA, No available; PTH, Parathyroid Hormone; U, urinary.
  • Supplementary Figure 1 Scatter plots of total serum calcium, parathyroid hormone (PTH) and the urinary calcium-to-creatinine ratio (UCa/Cr) in patients heterozygous for inactivating or activating mutations in the CASR gene. The reference ranges for each parameter are indicated by the horizontal bars. Scatter plots for presumed activating mutations are marked in red.


     European Society of Endocrinology

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    Scatter plots of total serum calcium and parathyroid hormone (PTH) levels for each phenotype observed in our cohort. The reference ranges considered were 8.5–10.2 mg/dL for total serum calcium and 8–51 pg/mL for PTH. Each patient is represented by a different symbol.

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    Pedigree of a family (ME133) with hyperparathyroidism. All five family members had normocalcemic hyperparathyroidism but only the proband and his father carried the p.Pro935_Gln945dup mutation.

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    Linear regression calcium and age at diagnosis (b) based on 65 patients with an inactivating mutation in the CASR gene. The correlation is significant (P < 0.01, r = 0.38).


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