Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
Front Endocrinol (Lausanne). 2024 Feb 29;15:1291160. doi: 10.3389/fendo.2024.1291160. eCollection 2024.
Although a monoallelic mutation in the calcium-sensing receptor () gene causes familial hypocalciuric hypercalcemia (FHH), the functional characterization of the identified mutation linked to the clinical response to calcimimetics therapy is still limited.
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) 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 .
Sanger sequencing of the , , and genes was performed in his family. The simulation model was used to predict the function of the identified mutant. studies, including immunoblotting, immunofluorescence, a cycloheximide chase study, Calbryte™ 520 Ca detection, and half-maximal effective concentration (EC), were examined.
This proband was found to carry a heterozygous missense in the cysteine-rich domain of , which was pathogenic based on the different software prediction models and ACGME criteria. The simulation model showed that mutation decreased its binding energy with Ca. Human mutation attenuated the stability of CASR protein, reduced the expression of p-ERK 1/2, and blunted the intracellular Ca response to gradient extracellular Ca (eCa) concentration. The EC study also demonstrated the correctable effect of calcimimetics on the function of the mutation.
This novel mutation causing FHH attenuates CASR stability, its binding affinity with Ca, and the response to eCa corrected by therapeutic calcimimetics.
尽管钙敏感受体（）基因的单等位基因突变可导致家族性低钙尿性高钙血症（FHH），但与钙敏感受体调节剂治疗临床反应相关的已鉴定突变的功能特征仍然有限。
一名 45 岁男性表现为中度高钙血症、低钙尿症和甲状旁腺激素（PTH）水平不适当升高，对西那卡塞（总血清钙（Ca）从 12.5 降至 10.1mg/dl）有良好反应。我们鉴定了遗传突变，并对其功能和病理生理机制进行了特征描述，然后将突变与钙敏感受体调节剂治疗联系起来。
对其家族进行了、和基因的 Sanger 测序。使用模拟模型预测鉴定的突变体的功能。进行了包括免疫印迹、免疫荧光、环己酰亚胺追踪研究、Calbryte™520 Ca 检测和半最大有效浓度（EC）在内的研究。
该先证者携带一个位于富含半胱氨酸域的杂合错义，根据不同的软件预测模型和 ACGME 标准，该突变具有致病性。模拟模型表明，突变降低了其与 Ca 的结合能。人突变减弱了 CASR 蛋白的稳定性，减少了 p-ERK 1/2 的表达，并使细胞内 Ca 对梯度细胞外 Ca（eCa）浓度的反应迟钝。EC 研究也表明钙敏感受体调节剂可纠正突变的功能。
这种新型的 FHH 致病突变削弱了 CASR 的稳定性、与 Ca 的结合亲和力以及治疗性钙敏感受体调节剂纠正的 eCa 反应。
