PMID- 35356007
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220504
IS  - 2472-1972 (Electronic)
IS  - 2472-1972 (Linking)
VI  - 6
IP  - 5
DP  - 2022 May 1
TI  - Functional Assessment of Calcium-Sensing Receptor Variants Confirms Familial 
      Hypocalciuric Hypercalcemia.
PG  - bvac025
LID - 10.1210/jendso/bvac025 [doi]
LID - bvac025
AB  - CONTEXT: In the clinic it is important to differentiate primary 
      hyperparathyroidism (PHPT) from the more benign, inherited disorder, familial 
      hypocalciuric hypercalcemia (FHH). Since the conditions may sometimes overlap 
      biochemically, identification of calcium-sensing receptor (CASR) gene variants 
      causative of FHH (but not PHPT) is the most decisive diagnostic aid. When novel 
      variants are identified, bioinformatics and functional assessment are required to 
      establish pathogenicity. OBJECTIVE: We identified 3 novel CASR transmembrane 
      domain missense variants, Thr699Asn, Arg701Gly, and Thr808Pro, in 3 probands 
      provisionally diagnosed with FHH and examined the variants using bioinformatics 
      and functional analysis. METHODS: Bioinformatics assessment utilized wANNOVAR 
      software. For functional characterization, each variant was cloned into a 
      mammalian expression vector; wild-type and variant receptors were transfected 
      into HEK293 cells, and their expression and cellular localization were assessed 
      by Western blotting and confocal immunofluorescence, respectively. Receptor 
      activation in HEK293 cells was determined using an IP-One ELISA assay following 
      stimulation with Ca(++) ions. RESULTS: Bioinformatics analysis of the variants 
      was unable to definitively assign pathogenicity. Compared with wild-type 
      receptor, all variants demonstrated impaired expression of mature receptor 
      reaching the cell surface and diminished activation at physiologically relevant 
      Ca(++) concentrations. CONCLUSION: Three CASR missense variants identified in 
      probands provisionally diagnosed with FHH result in receptor inactivation and are 
      therefore likely causative of FHH. Inactivation may be due to inadequate 
      processing/trafficking of mature receptor and/or conformational changes induced 
      by the variants affecting receptor signaling. This study demonstrates the value 
      of functional studies in assessing genetic variants identified in hypercalcemic 
      patients.
CI  - (c) The Author(s) 2022. Published by Oxford University Press on behalf of the 
      Endocrine Society.
FAU - Mullin, Benjamin H
AU  - Mullin BH
AUID- ORCID: 0000-0003-0743-770X
AD  - Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, 
      Nedlands, WA 6009, Australia.
AD  - School of Biomedical Sciences, University of Western Australia, Nedlands, WA 
      6009, Australia.
FAU - Pavlos, Nathan J
AU  - Pavlos NJ
AUID- ORCID: 0000-0001-7003-188X
AD  - School of Biomedical Sciences, University of Western Australia, Nedlands, WA 
      6009, Australia.
FAU - Brown, Suzanne J
AU  - Brown SJ
AUID- ORCID: 0000-0002-8413-561X
AD  - Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, 
      Nedlands, WA 6009, Australia.
FAU - Walsh, John P
AU  - Walsh JP
AUID- ORCID: 0000-0002-1766-2612
AD  - Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, 
      Nedlands, WA 6009, Australia.
AD  - Medical School, University of Western Australia, Nedlands, WA 6009, Australia.
FAU - McKellar, Ross A
AU  - McKellar RA
AD  - Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, 
      Nedlands, WA 6009, Australia.
FAU - Wilson, Scott G
AU  - Wilson SG
AUID- ORCID: 0000-0002-0357-1373
AD  - Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, 
      Nedlands, WA 6009, Australia.
AD  - School of Biomedical Sciences, University of Western Australia, Nedlands, WA 
      6009, Australia.
AD  - Department of Twin Research and Genetic Epidemiology, King's College London, 
      London WC2R 2LS, UK.
FAU - Ward, Bryan K
AU  - Ward BK
AUID- ORCID: 0000-0001-9251-2107
AD  - Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, 
      Nedlands, WA 6009, Australia.
AD  - Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII 
      Medical Centre, University of Western Australia, Nedlands, WA 6009, Australia.
LA  - eng
PT  - Journal Article
DEP - 20220218
PL  - United States
TA  - J Endocr Soc
JT  - Journal of the Endocrine Society
JID - 101697997
CIN - J Endocr Soc. 2022 Apr 04;6(6):bvac052. PMID: 35506149
PMC - PMC8962451
OTO - NOTNLM
OT  - IP-One ELISA assay
OT  - calcium-sensing receptor variants
OT  - familial hypocalciuric hypercalcemia
OT  - functional assessment
OT  - immunofluorescence
OT  - receptor expression
EDAT- 2022/04/01 06:00
MHDA- 2022/04/01 06:01
PMCR- 2022/02/18
CRDT- 2022/03/31 05:24
PHST- 2021/11/24 00:00 [received]
PHST- 2022/03/31 05:24 [entrez]
PHST- 2022/04/01 06:00 [pubmed]
PHST- 2022/04/01 06:01 [medline]
PHST- 2022/02/18 00:00 [pmc-release]
AID - bvac025 [pii]
AID - 10.1210/jendso/bvac025 [doi]
PST - epublish
SO  - J Endocr Soc. 2022 Feb 18;6(5):bvac025. doi: 10.1210/jendso/bvac025. eCollection 
      2022 May 1.