FMH, MAN, RB and RVT and contributed equally.
A homozygous inactivating calcium-sensing receptor mutation, Pro339Thr, is associated with isolated primary hyperparathyroidism: correlation between location of mutations and severity of hypercalcaemia
Article first published online: 16 NOV 2010
© 2010 Blackwell Publishing Ltd
Volume 73, Issue 6, pages 715–722, December 2010
How to Cite
Hannan, F. M., Nesbit, M. A., Christie, P. T., Lissens, W., Van der Schueren, B., Bex, M., Bouillon, R. and Thakker, R. V. (2010), A homozygous inactivating calcium-sensing receptor mutation, Pro339Thr, is associated with isolated primary hyperparathyroidism: correlation between location of mutations and severity of hypercalcaemia. Clinical Endocrinology, 73: 715–722. doi: 10.1111/j.1365-2265.2010.03870.x
- Issue published online: 16 NOV 2010
- Article first published online: 16 NOV 2010
- Accepted manuscript online: 16 SEP 2010 12:00AM EST
- (Received 29 April 2010; returned for revision 23 May 2010; finally revised 26 July 2010; accepted 17 August 2010)
Background Inactivating mutations of the calcium-sensing receptor (CaSR), a G-protein-coupled receptor with extracellular (ECD), transmembrane (TMD) and intracellular (ICD) domains, cause familial hypocalciuric hypercalcaemia, neonatal severe primary hyperparathyroidism and occasionally primary hyperparathyroidism in adults.
Objective To investigate a patient with typical symptomatic primary hyperparathyroidism for CaSR abnormalities.
Patient and design A 51-year-old woman with primary hyperparathyroidism was investigated for CaSR abnormalities as her severe hypercalcaemia (3·75 mm) persisted after the removal of two large parathyroid adenomas and she was the daughter of normocalcaemic consanguineous parents. Following informed consent, CASR mutational analysis was undertaken using leucocyte DNA. Wild-type and mutant CaSR constructs were expressed in human embryonic kidney (HEK) 293 cells and assessed by measuring their intracellular calcium responses to changes in extracellular calcium. Clinical data were pooled with previous studies to search for genotype–phenotype correlations.
Results The proband was homozygous for a Pro339Thr CaSR missense mutation, located in the ECD, and her normocalcaemic relatives were heterozygous. The mutant Thr339 CaSR had a rightward shift in its dose–response curve with a significantly higher EC50 = 3·18 mm ± 0·19 compared to the wild-type EC50 = 2·16 mm ± 0·1 (P < 0·01), consistent with a loss-of-function mutation. An analysis of CaSR mutations in patients with primary hyperparathyroidism revealed that those of the ECD were associated with a significantly greater hypercalcaemia that was less likely to be corrected after removal of the parathyroid tumours.
Conclusions A CaSR missense mutation causing a loss-of-receptor-function can cause symptomatic primary hyperparathyroidism in adulthood.