PMID- 18796518
OWN - NLM
STAT- MEDLINE
DCOM- 20090127
LR  - 20220330
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 93
IP  - 12
DP  - 2008 Dec
TI  - Novel inactivating mutations of the calcium-sensing receptor: the calcimimetic 
      NPS R-568 improves signal transduction of mutant receptors.
PG  - 4797-803
LID - 10.1210/jc.2008-1076 [doi]
AB  - CONTEXT AND OBJECTIVE: Inactivating mutations in the calcium-sensing receptor 
      (CaSR) gene cause neonatal severe hyperparathyroidism and familial hypocalciuric 
      hypercalcemia (FHH). The aims of the present study were the functional 
      characterization of novel mutations of the CaSR found in FHH patients, the 
      comparison of in vitro receptor function with clinical parameters, and the effect 
      of the allosteric calcimimetic NPS R-568 on the signaling of mutant receptors. 
      METHODS: Wild-type and mutant CaSRs (W530G, C568Y, W718X, M734R, L849P, Q926R, 
      and D1005N) were expressed in human embryonic kidney 293 cells. Receptor 
      signaling was studied by measuring intracellular free calcium in response to 
      different concentrations of extracellular calcium ([Ca(2+)](o)). RESULTS: Four 
      CaSR mutations (C568Y, W718X, M734R, and L849P) demonstrated a complete lack of a 
      [Ca(2+)](o)-induced cytosolic Ca(2+) response up to 30 mm [Ca(2+)](o), whereas 
      the CaSR mutants W530G, Q926R, and D1005N retained some sensitivity to 
      [Ca(2+)](o). There was no significant relation between the in vitro calcium 
      sensitivity, serum calcium, and intact PTH levels in the patients. Patients with 
      C-terminal CaSR mutations had a calcium to creatine ratio above the established 
      diagnostic threshold of 0.01 for FHH. The calcimimetic NPS R-568 enhanced the 
      responsiveness to [Ca(2+)](o) in CaSR mutants of the extracellular domain (W530G 
      and C568Y) as well as the intracellular C-terminal domain (Q926R and D1005N). 
      CONCLUSION: Therefore, calcimimetics might offer medical treatment for 
      symptomatic FHH patients, and more important, for patients with neonatal severe 
      hyperparathyroidism that harbor calcimimetic-sensitive CaSR mutants.
FAU - Rus, Ramona
AU  - Rus R
AD  - Division of Neuroendocrinology, Department of Neurosurgery, Friedrich-Alexander 
      University Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.
FAU - Haag, Christine
AU  - Haag C
FAU - Bumke-Vogt, Christiane
AU  - Bumke-Vogt C
FAU - Bahr, Volker
AU  - Bahr V
FAU - Mayr, Bernhard
AU  - Mayr B
FAU - Mohlig, Matthias
AU  - Mohlig M
FAU - Schulze, Egbert
AU  - Schulze E
FAU - Frank-Raue, Karin
AU  - Frank-Raue K
FAU - Raue, Friedhelm
AU  - Raue F
FAU - Schofl, Christof
AU  - Schofl C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080916
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (Aniline Compounds)
RN  - 0 (CASR protein, human)
RN  - 0 (N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine)
RN  - 0 (Phenethylamines)
RN  - 0 (Propylamines)
RN  - 0 (Receptors, Calcium-Sensing)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Aniline Compounds/*pharmacology
MH  - Blotting, Western
MH  - Calcium/agonists/blood
MH  - Cell Line
MH  - Humans
MH  - Hypercalcemia/genetics/physiopathology
MH  - Hypoparathyroidism/genetics/physiopathology
MH  - Mutagenesis, Site-Directed
MH  - *Mutation
MH  - Phenethylamines
MH  - Propylamines
MH  - Receptors, Calcium-Sensing/*genetics/*physiology
MH  - Signal Transduction/*drug effects/*genetics
EDAT- 2008/09/18 09:00
MHDA- 2009/01/28 09:00
CRDT- 2008/09/18 09:00
PHST- 2008/09/18 09:00 [pubmed]
PHST- 2009/01/28 09:00 [medline]
PHST- 2008/09/18 09:00 [entrez]
AID - jc.2008-1076 [pii]
AID - 10.1210/jc.2008-1076 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2008 Dec;93(12):4797-803. doi: 10.1210/jc.2008-1076. 
      Epub 2008 Sep 16.