PMID- 38487341
OWN - NLM
STAT- MEDLINE
DCOM- 20240318
LR  - 20240318
IS  - 1664-2392 (Print)
IS  - 1664-2392 (Electronic)
IS  - 1664-2392 (Linking)
VI  - 15
DP  - 2024
TI  - Identification and characterization of a novel CASR mutation causing familial 
      hypocalciuric hypercalcemia.
PG  - 1291160
LID - 10.3389/fendo.2024.1291160 [doi]
LID - 1291160
AB  - CONTEXT: Although a monoallelic mutation in the calcium-sensing receptor (CASR) 
      gene causes familial hypocalciuric hypercalcemia (FHH), the functional 
      characterization of the identified CASR mutation linked to the clinical response 
      to calcimimetics therapy is still limited. OBJECTIVE: A 45-year-old male 
      presenting with moderate hypercalcemia, hypocalciuria, and inappropriately high 
      parathyroid hormone (PTH) had a good response to cinacalcet (total serum calcium 
      (Ca(2+)) from 12.5 to 10.1 mg/dl). We identified the genetic mutation and 
      characterized the functional and pathophysiological mechanisms, and then linked 
      the mutation to calcimimetics treatment in vitro. DESIGN: Sanger sequencing of 
      the CASR, GNA11, and AP2S1 genes was performed in his family. The simulation 
      model was used to predict the function of the identified mutant. In vitro 
      studies, including immunoblotting, immunofluorescence, a cycloheximide chase 
      study, Calbryte 520 Ca(2+) detection, and half-maximal effective concentration 
      (EC(50)), were examined. RESULTS: This proband was found to carry a de novo 
      heterozygous missense I554N in the cysteine-rich domain of CASR, which was 
      pathogenic based on the different software prediction models and ACGME criteria. 
      The simulation model showed that CASR I554N mutation decreased its binding energy 
      with Ca(2+). Human CASR I554N mutation attenuated the stability of CASR protein, 
      reduced the expression of p-ERK 1/2, and blunted the intracellular Ca(2+) 
      response to gradient extracellular Ca(2+) (eCa(2+)) concentration. The EC(50) 
      study also demonstrated the correctable effect of calcimimetics on the function 
      of the CASR I554N mutation. CONCLUSION: This novel CASR I554N mutation causing 
      FHH attenuates CASR stability, its binding affinity with Ca(2+), and the response 
      to eCa(2+) corrected by therapeutic calcimimetics.
CI  - Copyright (c) 2024 Lin, Ding, Huang, Chen, Lee, Sung and Lin.
FAU - Lin, Chien-Ming
AU  - Lin CM
AD  - Department of Pediatrics, Tri-Service General Hospital, National Defense Medical 
      Center, Taipei, Taiwan.
FAU - Ding, Yi-Xuan
AU  - Ding YX
AD  - Department of Pediatrics, Tri-Service General Hospital, National Defense Medical 
      Center, Taipei, Taiwan.
FAU - Huang, Shih-Ming
AU  - Huang SM
AD  - Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
FAU - Chen, Ying-Chuan
AU  - Chen YC
AD  - Department of Physiology and Biophysics, National Defense Medical Center, Taipei, 
      Taiwan.
FAU - Lee, Hwei-Jen
AU  - Lee HJ
AD  - Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
FAU - Sung, Chih-Chien
AU  - Sung CC
AD  - Division of Nephrology, Department of Medicine, Tri-Service General Hospital, 
      National Defense Medical Center, Taipei, Taiwan.
FAU - Lin, Shih-Hua
AU  - Lin SH
AD  - Division of Nephrology, Department of Medicine, Tri-Service General Hospital, 
      National Defense Medical Center, Taipei, Taiwan.
LA  - eng
PT  - Case Reports
PT  - Journal Article
DEP - 20240229
PL  - Switzerland
TA  - Front Endocrinol (Lausanne)
JT  - Frontiers in endocrinology
JID - 101555782
RN  - 0 (Receptors, Calcium-Sensing)
RN  - SY7Q814VUP (Calcium)
RN  - 0 (CASR protein, human)
RN  - Hypocalciuric hypercalcemia, familial, type 1
SB  - IM
MH  - Male
MH  - Humans
MH  - Middle Aged
MH  - *Hypercalcemia/drug therapy/genetics/diagnosis/*congenital
MH  - Receptors, Calcium-Sensing/genetics/metabolism
MH  - Calcium/metabolism
MH  - Mutation
MH  - *Hyperparathyroidism
MH  - *Kidney Diseases
PMC - PMC10937390
OTO - NOTNLM
OT  - calcimimetics
OT  - calcium-sensing receptor
OT  - familial hypocalciuric hypercalcemia
OT  - half-maximal effective concentration
OT  - parathyroid hormone
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2024/03/15 06:43
MHDA- 2024/03/18 06:44
PMCR- 2024/01/01
CRDT- 2024/03/15 04:07
PHST- 2023/09/08 00:00 [received]
PHST- 2024/01/22 00:00 [accepted]
PHST- 2024/03/18 06:44 [medline]
PHST- 2024/03/15 06:43 [pubmed]
PHST- 2024/03/15 04:07 [entrez]
PHST- 2024/01/01 00:00 [pmc-release]
AID - 10.3389/fendo.2024.1291160 [doi]
PST - epublish
SO  - Front Endocrinol (Lausanne). 2024 Feb 29;15:1291160. doi: 
      10.3389/fendo.2024.1291160. eCollection 2024.