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A novel mutation in calcium-sensing receptor gene associated to hypercalcemia and hypercalciuria.

Mastromatteo E, Lamacchia O, Campo MR, Conserva A, Baorda F, Cinque L, Guarnieri V, Scillitani A, Cignarelli M - BMC Endocr Disord (2014)

Bottom Line: In two individuals, father and son, we found a novel heterozygous mutation in CaSR gene.The father was treated with Cinacalcet 90 mg/day, with a decrease of total serum calcemia from an average value of 12.2 mg/dl to 10.9 mg/dl.The impairment of the receptor activity is in keeping with the specific localization of the 972 residue in the C-terminal tail, assigned to the intracellular signalling, that on the basis of the our findings appears to be differently modulated in parathyroid gland and in kidney.

View Article: PubMed Central - PubMed

Affiliation: Unit of Endocrinology and Metabolic Diseases, Department of Medical and Surgical Sciences, University of Foggia, Italy, Viale Pinto, 1, 71122 Foggia, Italy. mauro.cignarelli@unifg.it.

ABSTRACT

Background: Familial Hyperparathyroidism (HPT) and Familial benign Hypocalciuric Hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. FHH has been demonstrated to be caused by inactivating mutations of calcium-sensing receptor (CaSR) gene, involved in PTH regulation as well as in renal calcium excretion.

Case presentation: In two individuals, father and son, we found a novel heterozygous mutation in CaSR gene. The hypercalcemia was present only in father, which, by contrast to the classic form of FHH showed hypercalciuria (from 300 to 600 mg/24 h in different evaluations) and a Calcium/Creatinine ratio of 0.031, instead of low or normal calciuria (<0.01 typical finding in FHH). His son showed the same mutation in CaSR gene, but no clinical signs or hypercalcemia although serum ionized calcium levels were close to the upper limit of normal values (1.30 mmol/L: normal range: 1.12-1.31 mmol/L). Sequence analysis revealed a point mutation at codon 972 of CaSR gene (chromosome 3q), located within cytoplasmic domain of the CaSR, that changes Threonine with Methionine. The father was treated with Cinacalcet 90 mg/day, with a decrease of total serum calcemia from an average value of 12.2 mg/dl to 10.9 mg/dl.

Conclusion: This is a case of a novel inactivating point mutation of CaSR gene that determines an atypical clinical presentation of FHH, characterized by hypercalcemia, hypercalciuria and inadequate normal PTH levels. Functional assay demonstrated that the 972 M variant influenced the maturation of the protein, in terms of the post-translational glycosylation. The impairment of the receptor activity is in keeping with the specific localization of the 972 residue in the C-terminal tail, assigned to the intracellular signalling, that on the basis of the our findings appears to be differently modulated in parathyroid gland and in kidney.

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Family tree of family under study. Black box indicates the presence of PHPT, the arrow the presence of the mutation (see text for clinical details).
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Fig2: Family tree of family under study. Black box indicates the presence of PHPT, the arrow the presence of the mutation (see text for clinical details).

Mentions: The patient was treated for 7 months with Cinacalcet 90 mg/day, since at that time we ignored the existence of the CaSR mutation. However, although Cinacalcet is not indicated for FHH treatment, we obtained a slight decrease of calcemia, but the therapy was stopped because of side effects appearance (hypotension, nausea). Subsequently, he refused other specific therapies. During a 4 years follow-up period hypercalcemia, hypercalciuria and normal levels of PTH persisted. A heterozygous mutation in exon 7 of the CaSR gene was found, predicting a p.T972M amino acid substitution in cytoplasmic tail of CaSR (Figure 1). The same mutation we found in one of his three screened sons, a 41-year-old men (Figure 2), who is currently asymptomatic and shows serum ionized calcium level of 1.30 mmol/L, close to the upper normal limit (n.v. 1.12-1.31), normal calciuria (195 mg/24 h) and PTH, but also a 25 hydroxy-Vitamin D3 deficiency (12.3 ng/ml) (Table 2).Figure 1


A novel mutation in calcium-sensing receptor gene associated to hypercalcemia and hypercalciuria.

Mastromatteo E, Lamacchia O, Campo MR, Conserva A, Baorda F, Cinque L, Guarnieri V, Scillitani A, Cignarelli M - BMC Endocr Disord (2014)

Family tree of family under study. Black box indicates the presence of PHPT, the arrow the presence of the mutation (see text for clinical details).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4197257&req=5

Fig2: Family tree of family under study. Black box indicates the presence of PHPT, the arrow the presence of the mutation (see text for clinical details).
Mentions: The patient was treated for 7 months with Cinacalcet 90 mg/day, since at that time we ignored the existence of the CaSR mutation. However, although Cinacalcet is not indicated for FHH treatment, we obtained a slight decrease of calcemia, but the therapy was stopped because of side effects appearance (hypotension, nausea). Subsequently, he refused other specific therapies. During a 4 years follow-up period hypercalcemia, hypercalciuria and normal levels of PTH persisted. A heterozygous mutation in exon 7 of the CaSR gene was found, predicting a p.T972M amino acid substitution in cytoplasmic tail of CaSR (Figure 1). The same mutation we found in one of his three screened sons, a 41-year-old men (Figure 2), who is currently asymptomatic and shows serum ionized calcium level of 1.30 mmol/L, close to the upper normal limit (n.v. 1.12-1.31), normal calciuria (195 mg/24 h) and PTH, but also a 25 hydroxy-Vitamin D3 deficiency (12.3 ng/ml) (Table 2).Figure 1

Bottom Line: In two individuals, father and son, we found a novel heterozygous mutation in CaSR gene.The father was treated with Cinacalcet 90 mg/day, with a decrease of total serum calcemia from an average value of 12.2 mg/dl to 10.9 mg/dl.The impairment of the receptor activity is in keeping with the specific localization of the 972 residue in the C-terminal tail, assigned to the intracellular signalling, that on the basis of the our findings appears to be differently modulated in parathyroid gland and in kidney.

View Article: PubMed Central - PubMed

Affiliation: Unit of Endocrinology and Metabolic Diseases, Department of Medical and Surgical Sciences, University of Foggia, Italy, Viale Pinto, 1, 71122 Foggia, Italy. mauro.cignarelli@unifg.it.

ABSTRACT

Background: Familial Hyperparathyroidism (HPT) and Familial benign Hypocalciuric Hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. FHH has been demonstrated to be caused by inactivating mutations of calcium-sensing receptor (CaSR) gene, involved in PTH regulation as well as in renal calcium excretion.

Case presentation: In two individuals, father and son, we found a novel heterozygous mutation in CaSR gene. The hypercalcemia was present only in father, which, by contrast to the classic form of FHH showed hypercalciuria (from 300 to 600 mg/24 h in different evaluations) and a Calcium/Creatinine ratio of 0.031, instead of low or normal calciuria (<0.01 typical finding in FHH). His son showed the same mutation in CaSR gene, but no clinical signs or hypercalcemia although serum ionized calcium levels were close to the upper limit of normal values (1.30 mmol/L: normal range: 1.12-1.31 mmol/L). Sequence analysis revealed a point mutation at codon 972 of CaSR gene (chromosome 3q), located within cytoplasmic domain of the CaSR, that changes Threonine with Methionine. The father was treated with Cinacalcet 90 mg/day, with a decrease of total serum calcemia from an average value of 12.2 mg/dl to 10.9 mg/dl.

Conclusion: This is a case of a novel inactivating point mutation of CaSR gene that determines an atypical clinical presentation of FHH, characterized by hypercalcemia, hypercalciuria and inadequate normal PTH levels. Functional assay demonstrated that the 972 M variant influenced the maturation of the protein, in terms of the post-translational glycosylation. The impairment of the receptor activity is in keeping with the specific localization of the 972 residue in the C-terminal tail, assigned to the intracellular signalling, that on the basis of the our findings appears to be differently modulated in parathyroid gland and in kidney.

Show MeSH
Related in: MedlinePlus