Mutations of calcium-sensing receptor gene: two novel mutations and overview of impact on calcium homeostasis.

[familial hypocalciuric hypercalcemia]

Genetic disorders of calcium metabolism arise in a familial or sporadic setting . The calcium-sensing receptor (CASR ) plays a key role in maintaining calcium homeostasis and study of the CASR gene can be clinically useful in determining etiology and appropriate therapeutic approaches . We report two cases of novel CASR gene mutations that illustrate the varying clinical presentations and discuss these in terms of the current understanding of CASR function .A 16 -year -old patient had mild hypercalcemia associated with low -normal urinary calcium excretion and normal-to -high parathyroid hormone (PTH ) levels . Because of negative family history , familial hypocalciuric hypercalcemia was originally excluded . The second patient was a 54 -year -old man with symptomatic hypocalcemia , hyperphosphatemia , low PTH , and mild hypercalciuria . Familial investigation revealed the same phenotype in the patient 's sister . The coding region of the CASR gene was sequenced in both probands and their available first -degree relatives .The first patient had a novel heterozygous inactivating CASR mutation in exon 4 , which predicted a p .A 423 K change ; genetic analysis was negative in the parents . The second patient had a novel heterozygous activating CASR mutation in exon 6 , which predicted a p .E 556 K change ; the affected sister of the proband was also positive .We reported two novel heterozygous mutations of the CASR gene , an inactivating mutation in exon 4 and the first activating mutation reported to date in exon 6 . These cases illustrate the importance of genetic testing of CASR gene to aid correct diagnosis and to assist in clinical management .