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

BMC Endocrine Disorders

Mauro Cignarelli¹  Alfredo Scillitani²  Vito Guarnieri³  Luigia Cinque³  Filomena Baorda³  Antonella Conserva¹  Michela Rosaria Campo¹  Olga Lamacchia¹  Eugenio Mastromatteo¹ 

[1] Unit of Endocrinology and Metabolic Diseases, Department of Medical and Surgical Sciences, University of Foggia, Italy, Viale Pinto, 1, 71122 Foggia, Italy;Unit of Endocrinology and Metabolic Diseases IRCCS “Casa Sollievo della Sofferenza” Hospital viale Padre Pio, 71013 San Giovanni Rotondo (FG), Italy;Medical Genetics Service IRCCS “Casa Sollievo della Sofferenza” Hospital viale Padre Pio, 71013 San Giovanni Rotondo (FG), Italy

关键词: Hypocalciuria;    Hypercalciuria;    Hypercalcemia;    FHH;    Hyperparathyroidism;    CaSR gene;   

Others  :  1084922
DOI  :  10.1186/1472-6823-14-81

 received in 2014-06-24, accepted in 2014-09-29,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Mastromatteo et al.; licensee BioMed Central Ltd.

【 图 表 】

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