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Familial benign hypocalciuric hypercalcemia (FBHH), in which calcium homeostasis is disordered, can be distinguished from mild primary hyperparathyroidism by the finding of a heterozygous loss-of-function mutation in the calcium-sensing receptor (CaSR). Here, we report a Polish kindred with FBHH, the proband of which had undergone an unsuccessful parathyroidectomy. Direct sequence analysis of exon 4 of her CASR gene identified a heterozygous R227Q mutation in the extracellular domain of the receptor. This mutation segregated with other affected family members. A de novo heterozygous R227L mutation had previously been identified in a case of neonatal hyperparathyroidism. We performed a functional analysis by transiently transfecting wild-type and mutant (R227Q, R227L) CaSRs in human embryonic kidney (HEK293) cells. Both mutant receptors were expressed at a similar level to that of the wild-type, demonstrated a 160-kDa molecular species consistent with having undergone full maturation, and were visualized on the cell surface. Although both mutants were impaired in their MAPK responses to increasing extracellular calcium concentrations relative to wild type, this was more marked for R227L (EC(50) = 9.7 mM) than R227Q (EC(50) = 7.9 mM) relative to wild type (EC(50) = 3.7 mM). When cotransfected with wild-type CaSR to mimic the heterozygous state, the curves for both R227Q and R227L were right shifted intermediate to the curves for wild type and the respective mutant. This differential responsiveness may account, in part, for the markedly different clinical presentation of the R227Q mutation, classic FBHH, vs. the neonatal hyperparathyroidism of the R227L mutation.

the journal of clinical endocrinology and metabolism/journal of clinical endocrinology and metabolism

Functional Characterization of Calcium-Sensing Receptor Codon 227 Mutations Presenting as Either Familial (Benign) Hypocalciuric Hypercalcemia or Neonatal Hyperparathyroidism