title: A homozygous inactivating calcium-sensing receptor mutation, Pro339Thr, is associated with isolated primary hyperparathyroidism: correlation between location of mutations and severity of hypercalcaemia.
abstract: 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 EC(50) = 3·18 mm ± 0·19 compared to the wild-type EC(50) = 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.
authors.affiliation: Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: Fadil M
authors.initials: FM
authors.lastname: Hannan
authors.forename: M A
authors.initials: MA
authors.lastname: Nesbit
authors.forename: Paul T
authors.initials: PT
authors.lastname: Christie
authors.forename: Willy
authors.initials: W
authors.lastname: Lissens
authors.forename: Bart
authors.initials: B
authors.lastname: Van der Schueren
authors.forename: Marie
authors.initials: M
authors.lastname: Bex
authors.forename: Roger
authors.initials: R
authors.lastname: Bouillon
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics*; D049950:Hyperparathyroidism, Primary / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D044169:Receptors, Calcium-Sensing