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Abstract: SA-PO743

Identification and Characterization of a Novel CASR Mutation Causing Familial Hypocalciuric Hypercalcemia

Session Information

Category: Fluid, Electrolytes, and Acid-Base Disorders

  • 1102 Fluid, Electrolyte, and Acid-Base Disorders: Clinical


  • Lin, Shih-Hua P., Tri-Service General Hospital Department of Internal Medicine, Taipei, Taiwan
  • Lin, Chien-Ming, Tri-Service General Hospital Department of Internal Medicine, Taipei, Taiwan
  • Sung, Chih-Chien, Tri-Service General Hospital Department of Internal Medicine, Taipei, Taiwan

Although familial hypocalciuric hypercalcemia type 1 (FHH1) is primarily caused by monoallelic mutation in calcium-sensing receptor (CASR) gene, the characterization of the newly-identified CaSR mutation linked to clinical response to calcimimetics remains limited.


A 45-year-old male presenting with hypercalcemia, hypocalciuria, and inappropriately high parathyroid hormone (PTH) had a good response to cinacalcet (total serum calcium from 12.5 to 10.1 mg/dl). Sanger sequencing of CASR, GNA11, and AP2S1 genes was performed in this family. The simulation model was used to predict the function of the identified mutant. The in vitro studies including immunoblotting, immunofluorescence, cycloheximide chase study, Calbryte™ 520 calcium (Ca2+) detection, and half-maximal effective concentration (EC50) were examined.


The patient was identified to carry a de novo heterozygous CASR I554N mutation, located in the cysteine-rich domain (residues 542–612) crucial to affect the ligands (Ca2+) binding. This missense mutation was pathogenic based on the different software prediction models and ACGME criteria. The simulation model showed CASR I554N mutation decreased its binding energy with Ca2+. Human CASR I554N mutation attenuated the stability of CASR protein, reduced the expression of p-ERK 1/2, and blunted the intracellular Ca2+ response to gradient extracellular Ca2+ (eCa2+) concentration. EC50 study also showed calcimimetics rescued the function of CASR I554N mutation.


This novel CASR I554N mutation decreases CASR stability and its binding affinity with Ca2+. Its correction of blunt response to eCa2+ by calcimimetics may support the therapeutic effect of cinacalcet for this patient.


  • Government Support – Non-U.S.