Loss-of-function and gain-of-function mutations of calcium-sensing receptor: functional analysis and the effect of allosteric modulators NPS R-568 and NPS 2143.

[familial hypocalciuric hypercalcemia]

Activating mutations in the calcium-sensing receptor (CASR ) gene cause autosomal dominant hypoparathyroidism , and heterozygous inactivating CASR mutations cause familial hypocalciuric hypercalcemia . Recently , there has been a focus on the use of allosteric modulators to restore the functional activity of mutant CASRs . In this study , the effect of allosteric modulators NPS R-568 and NPS 2143 on CASR mutants was studied in vitro .DNA sequence analysis of the CASR gene was undertaken in autosomal dominant hypoparathyroidism and familial hypocalciuric hypercalcemia Japanese patients , and the functional consequences for the Gi -MAPK pathway and cell surface expression of CASR were determined . Furthermore , we studied the effect of NPS R-568 and NPS 2143 on the signal transduction activity and cell surface expression of each mutant CASR .We identified 3 activating mutations (S 122 C , P 569 H , and I 839 T ) and 2 inactivating mutations (A 110 T and R 172 G ) in patients . The activating and inactivating mutations caused leftward and rightward shifts , respectively , in the dose-response curves of the signaling pathway . NPS R-568 rescued the signal transduction capacity of 2 inactivating mutants without increasing cell surface expression levels . NPS 2143 suppressed the enhanced activity of the activating mutants without altering cell surface expression levels , although A 843 E , which is a constitutively active mutant , was suppressed to a lesser degree .We have identified 4 novel mutations of CASR . Moreover , our results indicate that allosteric modulators can restore the activity of the loss - and gain-of-function mutant CASRs , identified in this study .

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Diseases presenting "and heterozygous inactivating casr mutations cause familial hypocalciuric hypercalcemia" symptom

familial hypocalciuric hypercalcemia

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