A novel gain-of-function mutation (F821L) in the transmembrane domain of calcium-sensing receptor is a cause of severe sporadic hypoparathyroidism.
Gain-of-function mutations of the extracellular calcium (Ca(2+)e)-sensing receptor (CaR) have been identified in patients with familial and sporadic hypercalciuric hypocalcaemia. We describe a patient with sporadic severe hypercalciuric hypocalcaemia with undetectable or very low levels of serum parathyroid hormone, carrying a de novo heterozygous missense mutation ( F821L), localized in the sixth transmembrane domain of CaR. Analysis of in vitro functional properties of the mutant receptor to measure Ca(2+)e-evoked changes in intracellular Ca(2+) revealed a leftward shift in the concentration-response curve for the mutant compared to wild-type receptor.


CONCLUSIONS
the F821Lmutation is therefore a novel gain-of-function mutation which can cause severe hypoparathyroidism. Thiazide diuretics lowered urinary calcium excretion of the patient treated with calcium supplementation and 1alpha-hydroxyvitamin D(3.)
Shiohara
Masaaki
M
Department of Paediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, 390-8621 Matsumoto, Japan. mjshio@poa.matsumoto.ne.jp
Mori
Tetsuo
T
Mei
Bai
B
Brown
Edward M
EM
Watanabe
Tomoyuki
T
Yasuda
Toshiyuki
T
D002118:Calcium / Q000097:blood* / Q000652:urine; D006801:Humans; D007011:Hypoparathyroidism / Q000097:blood / Q000209:etiology*; D007231:Infant, Newborn; D008297:Male; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D017422:Sequence Analysis, DNA
C095550:CASR protein, human; D044169:Receptors, Calcium-Sensing; D002118:Calcium