Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Clin Endocrinol (Oxf). 2010 Dec;73(6):715-22. doi: 10.1111/j.1365-2265.2010.03870.x.
Inactivating mutations of the calcium-sensing receptor (CaSR), a G-protein-coupled receptor with extracellular (ECD), transmembrane (TMD) and intracellular (ICD) domains, cause familial hypocalciuric hypercalcaemia, neonatal severe primary hyperparathyroidism and occasionally primary hyperparathyroidism in adults.
To investigate a patient with typical symptomatic primary hyperparathyroidism for CaSR abnormalities. PATIENT AND DESIGN: A 51-year-old woman with primary hyperparathyroidism was investigated for CaSR abnormalities as her severe hypercalcaemia (3·75 mm) persisted after the removal of two large parathyroid adenomas and she was the daughter of normocalcaemic consanguineous parents. Following informed consent, CASR mutational analysis was undertaken using leucocyte DNA. Wild-type and mutant CaSR constructs were expressed in human embryonic kidney (HEK) 293 cells and assessed by measuring their intracellular calcium responses to changes in extracellular calcium. Clinical data were pooled with previous studies to search for genotype-phenotype correlations.
The proband was homozygous for a Pro339Thr CaSR missense mutation, located in the ECD, and her normocalcaemic relatives were heterozygous. The mutant Thr339 CaSR had a rightward shift in its dose-response curve with a significantly higher EC(50) = 3·18 mm ± 0·19 compared to the wild-type EC(50) = 2·16 mm ± 0·1 (P < 0·01), consistent with a loss-of-function mutation. An analysis of CaSR mutations in patients with primary hyperparathyroidism revealed that those of the ECD were associated with a significantly greater hypercalcaemia that was less likely to be corrected after removal of the parathyroid tumours.
A CaSR missense mutation causing a loss-of-receptor-function can cause symptomatic primary hyperparathyroidism in adulthood.
钙敏感受体 (CaSR) 是一种具有细胞外 (ECD)、跨膜 (TMD) 和细胞内 (ICD) 结构域的 G 蛋白偶联受体，其失活突变可导致家族性低钙尿性高钙血症、新生儿严重原发性甲状旁腺功能亢进症，偶尔也会导致成人原发性甲状旁腺功能亢进症。
研究一位具有典型症状的原发性甲状旁腺功能亢进症患者的 CaSR 异常情况。
一名 51 岁女性患有原发性甲状旁腺功能亢进症，其严重高钙血症（3.75mmol/L）在切除两个大甲状旁腺腺瘤后仍持续存在，且其为血钙正常的近亲结婚父母的女儿。在获得知情同意后，使用白细胞 DNA 进行 CaSR 突变分析。通过测量细胞外钙浓度变化引起的细胞内钙反应，表达野生型和突变型 CaSR 构建体，并在人胚肾 (HEK) 293 细胞中进行评估。将临床数据与之前的研究结果进行汇总，以寻找基因型-表型相关性。
该先证者为 ECD 中 Pro339Thr CaSR 错义突变的纯合子，其血钙正常的亲属为杂合子。突变的 Thr339 CaSR 其剂量反应曲线右移，EC50 值明显升高（3.18mmol/L±0.19 比野生型的 2.16mmol/L±0.1，P<0.01），提示存在功能丧失型突变。对原发性甲状旁腺功能亢进症患者的 CaSR 突变分析表明，ECD 中的突变与更高的高钙血症显著相关，且肿瘤切除后血钙更难以纠正。
导致受体功能丧失的 CaSR 错义突变可导致成人发生有症状的原发性甲状旁腺功能亢进症。
