PMID- 23169696
OWN - NLM
STAT- MEDLINE
DCOM- 20130305
LR  - 20191210
IS  - 1479-683X (Electronic)
IS  - 0804-4643 (Linking)
VI  - 168
IP  - 2
DP  - 2013 Feb
TI  - Two novel mutations of the calcium-sensing receptor gene affecting the same amino 
      acid position lead to opposite phenotypes and reveal the importance of p.N802 on 
      receptor activity.
PG  - K27-34
LID - 10.1530/EJE-12-0714 [doi]
AB  - OBJECTIVE: Gain-of-function mutations of the calcium-sensing receptor (CASR) gene 
      have been identified in patients with sporadic or familial autosomal dominant 
      hypocalcemia (ADH). Inactivating mutations of the CASR gene cause familial 
      hypocalciuric hypercalcemia (FHH). Here, we report two novel CASR mutations 
      affecting the same amino acid (p.N802); one causes ADH and the other atypical 
      FHH. PATIENTS AND METHODS: The first patient, an 11-year-old girl suffering from 
      hypocalcemia, developed nephrocalcinosis when she was only 5 years old. The 
      second patient is a 30-year-old woman who presented with mild hypercalcemia. PCR 
      amplification of CASR coding exons and direct sequencing of PCR products were 
      used to identify mutations. Site-directed mutagenesis was used to generate 
      mutated CASR cDNAs in an expression plasmid. Using the MAPK assay system and 
      transient transfection of Cos-7 cells with wild-type (WT) and mutated CASR, we 
      studied the responses of these mutated receptors to extracellular Ca(2+) and to 
      the negative allosteric CASR modulator, NPS2143. RESULTS: Two heterozygous 
      missense mutations (p.N802I and p.N802S) affecting a residue in the sixth 
      transmembrane domain of CASR were identified. In functional tests, the response 
      of the p.N802S mutant to calcium was typical of an inactivating mutation. 
      However, the p.N802I mutant had 70% of the maximally stimulated WT receptor 
      activity even in the absence of extracellular calcium. This constitutive activity 
      was only partially inhibited by the inhibitor, NPS2143. CONCLUSIONS: The 
      asparagine at amino acid position 802 appears to be essential for the activity of 
      the CASR protein and is implicated in the mechanism of CASR signaling.
FAU - Lia-Baldini, Anne-Sophie
AU  - Lia-Baldini AS
AD  - EA 6309 - Maintenance Myelinique et Neuropathies Peripheriques, Faculte de 
      Medecine - Biochimie, Universite de Limoges, 6eme etage, 2 rue du Dr Marcland, 
      87025 Limoges, France. asliabaldini@unilim.fr
FAU - Magdelaine, Corinne
AU  - Magdelaine C
FAU - Nizou, Angelique
AU  - Nizou A
FAU - Airault, Coraline
AU  - Airault C
FAU - Salles, Jean-Pierre
AU  - Salles JP
FAU - Moulin, Pierre
AU  - Moulin P
FAU - Delemer, Brigitte
AU  - Delemer B
FAU - Aitouares, Mina
AU  - Aitouares M
FAU - Funalot, Benoit
AU  - Funalot B
FAU - Sturtz, Franck
AU  - Sturtz F
FAU - Lienhardt-Roussie, Anne
AU  - Lienhardt-Roussie A
LA  - eng
PT  - Case Reports
PT  - Journal Article
DEP - 20130117
PL  - England
TA  - Eur J Endocrinol
JT  - European journal of endocrinology
JID - 9423848
RN  - 0 (Receptors, Calcium-Sensing)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Adult
MH  - Animals
MH  - COS Cells
MH  - Calcium/*metabolism
MH  - Child
MH  - Chlorocebus aethiops
MH  - Female
MH  - Humans
MH  - Hypercalcemia/*genetics/metabolism
MH  - Mutagenesis, Site-Directed
MH  - *Mutation
MH  - Nephrocalcinosis/*genetics/metabolism
MH  - Phenotype
MH  - Receptors, Calcium-Sensing/*genetics/metabolism
MH  - Transfection
EDAT- 2012/11/22 06:00
MHDA- 2013/03/06 06:00
CRDT- 2012/11/22 06:00
PHST- 2012/11/22 06:00 [entrez]
PHST- 2012/11/22 06:00 [pubmed]
PHST- 2013/03/06 06:00 [medline]
AID - EJE-12-0714 [pii]
AID - 10.1530/EJE-12-0714 [doi]
PST - epublish
SO  - Eur J Endocrinol. 2013 Jan 17;168(2):K27-34. doi: 10.1530/EJE-12-0714. Print 2013 
      Feb.