A novel mutation in the calcium-sensing receptor in a French family with familial hypocalciuric hypercalcaemia

• Published in: European journal of endocrinology Vol. 165; no. 2; pp. 359 - 363
• Main Authors: Al-Salameh, Abdallah, Cetani, Filomena, Pardi, Elena, Vulpoi, Carmen, Pierre, Peggy, de Calan, Loïc, Guyetant, Serge, Jeunemaitre, Xavier, Lecomte, Pierre
• Format: Journal Article
• Language: English
• Published: Bristol BioScientifica 01.08.2011; European Society of Endocrinology
• Subjects: Adult; Amino Acid Sequence; Animals; Biological and medical sciences; Case Report; Cercopithecus aethiops; COS Cells; Endocrinopathies; Family; Female; France; Fundamental and applied biological sciences. Psychology; Humans; Hypercalcemia - congenital; Hypercalcemia - genetics; Male; Medical sciences; Models, Biological; Molecular Sequence Data; Pedigree; Receptors, Calcium-Sensing - genetics; Transfection; Vertebrates: endocrinology; France; Europe; Hydroelectrolytic balance disorder; Calcium; Family study; Inorganic element; Hypercalcemia; Metabolic disorder; French; Hypocalciuria; Family environment; Genetics; Mutation; Calcium-sensing receptor; Endocrinology
• ISSN: 0804-4643; 1479-683X
• DOI: 10.1530/EJE-11-0141

ObjectiveThe calcium-sensing receptor (CASR) has an important role in calcium homoeostasis by controlling PTH secretion and renal calcium handling. Inactivating mutations in the CASR gene (HGNC ID: 1514) cause familial hypocalciuric hypercalcaemia (FHH). We present a case of FHH patient to describe a novel mutation in the CASR.Subjects and methodsA 34-year-old patient was referred because of recurrent hypercalcaemia after resection of two hyperplastic parathyroids. Extensive evaluation found elevated PTH and low calcium/creatinine clearance ratio. One of her three children had high serum calcium concentrations. Genetic studies were performed by PCR amplification of CASR coding exons and direct sequencing of PCR products. Transient transfection of the wild-type (WT) CASR and the mutant CASR into COS-7 was performed to assess functional impact of the mutation and the capacity of either protein to mediate increases in cellular levels of inositol phosphates (IPs).ResultsCASR sequencing found a previously undescribed heterozygous base substitution, determining a change of threonine to isoleucine at codon 550 (p.T550I) in the sixth exon. In contrast to those transfected with WT CASR, which showed a five- to eightfold increase in total IPs at high levels of calcium, COS-7 cells transfected with the (p.T550I) mutant showed no increase confirming to the inactivating nature of the mutation. COS-7 cells co-transfected with the WT and the (p.T550I) mutant showed an intermediate response suggesting a possible dominant negative effect.ConclusionThis case report presents a not-yet-described mutation in the cysteine-rich region of the CASR extracellular domain, a mutation with a possible dominant negative effect.