A homozygous inactivating calcium-sensing receptor mutation, Pro339Thr, is associated with isolated primary hyperparathyroidism: correlation between location of mutations and severity of hypercalcaemia

Fadil Mohammed Hannan (1) , M. Andrew Nesbit (1) , Paul Christie (1) , Willy Lissens (2) , Bart Vanderschueren (3) , Marie Bex (1) , Roger Bouillon (1) , Rajesh V Thakker (1)

1 Nuffield Department of Clinical Medicine [Oxford]
2 Center for Medical Genetics
3 Clinic and Laboratory of Experimental Medicine and Endocrinology

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 mmol/l) persisted after the removal of 2 large parathyroid adenomas and she was the daughter of normocalcaemic consanguineous parents. Following informed consent, CASR mutational analysis was undertaken using leukocyte 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 adult onset symptomatic primary hyperparathyroidism.

Mots clés: Medicine

Fadil Mohammed Hannan, M. Andrew Nesbit, Paul Christie, Willy Lissens, Bart Vanderschueren, et al.. 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, 2010, 73 (6), pp.715. ⟨10.1111/j.1365-2265.2010.03870.x⟩. ⟨hal-00593440⟩