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

Antoni Wystrychowski, Svetlana Pidasheva, Lucie Canaff, Jerzy Chudek, Franciszek Kokot, Andrzej Wicek and Geoffrey N. Hendy

Departments of Nephrology, Endocrinology, and Metabolic Diseases (A.Wy., J.C., F.K., A.Wi.), Medical University of Silesia, Katowice, 40-055 Poland; and Departments of Medicine, Human Genetics, and Physiology (S.P., L.C., G.N.H.), McGill University and Calcium Research Laboratory, Royal Victoria Hospital, Montréal, Québec, H3A 1A1 Canada

Address all correspondence and requests for reprints to: Dr. Geoffrey N. Hendy, Calcium Research Laboratory, Royal Victoria Hospital, Room H4.67, 687 Pine Avenue West, Montreal, Quebec H3A 1A1 Canada. E-mail: geoffrey.hendy{at}mcgill.ca.

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 (EC₅₀ = 9.7 mM) than R227Q (EC₅₀ = 7.9 mM) relative to wild type (EC₅₀ = 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.

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