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

被引:13
|
作者
Mastromatteo, Eugenio [1 ]
Lamacchia, Olga [1 ]
Campo, Michela Rosaria [1 ]
Conserva, Antonella [1 ]
Baorda, Filomena [2 ]
Cinque, Luigia [2 ]
Guarnieri, Vito [2 ]
Scillitani, Alfredo [3 ]
Cignarelli, Mauro [1 ]
机构
[1] Univ Foggia, Dept Med & Surg Sci, Unit Endocrinol & Metab Dis, I-71122 Foggia, Italy
[2] IRCCS, Casa Sollievo della Sofferenza Hosp, Med Genet Serv, I-71013 San Giovanni Rotondo, FG, Italy
[3] IRCCS, Casa Sollievo della Sofferenza Hosp, Unit Endocrinol & Metab Dis, I-71013 San Giovanni Rotondo, FG, Italy
来源
BMC ENDOCRINE DISORDERS | 2014年 / 14卷
关键词
CaSR gene; Hyperparathyroidism; FHH; Hypercalcemia; Hypercalciuria; Hypocalciuria; N-LINKED GLYCOSYLATION; FAMILIAL HYPERCALCEMIA; CELL-SURFACE; CASR; EXPRESSION; MAPS;
D O I
10.1186/1472-6823-14-81
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
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.
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页数:6
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