title: A novel mutation in calcium-sensing receptor gene associated to hypercalcemia and hypercalciuria.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mastromatteo
authors.forename: Olga
authors.initials: O
authors.lastname: Lamacchia
authors.forename: Michela Rosaria
authors.initials: MR
authors.lastname: Campo
authors.forename: Antonella
authors.initials: A
authors.lastname: Conserva
authors.forename: Filomena
authors.initials: F
authors.lastname: Baorda
authors.forename: Luigia
authors.initials: L
authors.lastname: Cinque
authors.forename: Vito
authors.initials: V
authors.lastname: Guarnieri
authors.forename: Alfredo
authors.initials: A
authors.lastname: Scillitani
authors.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.
authors.forename: Mauro
authors.initials: M
authors.lastname: Cignarelli
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D057966:Calcimimetic Agents / Q000627:therapeutic use*; D000069449:Cinacalcet; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D006934:Hypercalcemia / Q000151:congenital* / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D053565:Hypercalciuria / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use*; D010281:Parathyroid Hormone / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017354:Point Mutation; D044169:Receptors, Calcium-Sensing / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C095550:CASR protein, human; D057966:Calcimimetic Agents; D005819:Genetic Markers; D009281:Naphthalenes; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D000069449:Cinacalcet