Benson Matthew R, Wyatt Rachael A, Levine Michael A, Gorvin Caroline M
Division of Endocrinology, Diabetes & Metabolism, Nemours Children's Health, Jacksonville, FL 32207, United States.
Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham, B15 2TT, United Kingdom.
J Bone Miner Res. 2025 Feb 2;40(2):270-282. doi: 10.1093/jbmr/zjae199.
Autosomal dominant hypocalcemia (ADH) is due to enhanced calcium-dependent signaling caused by heterozygous gain-of-function (GOF) variants in the CASR gene (ADH1) or in the GNA11 gene, encoding Gα11 (ADH2). Both ADH1 and ADH2 are associated with hypocalcemia and normal or inappropriately low levels of circulating PTH. ADH1 patients typically manifest hypercalciuria, while ADH2 is associated with short stature in approximately 42% of cases. We evaluated a 10-yr-old boy with hypoparathyroidism and short stature. Biochemical analyses revealed hypocalcemia, hyperphosphatemia, and inconsistent hypercalciuria. Genetic analyses revealed a de novo heterozygous p.Leu723Arg variant in CASR. We characterized the expression of recombinant WT and Leu723Arg calcium-sensing receptor (CaSR) proteins in HEK293 cells and assessed G protein activation in vitro by CaSR using bioluminescence resonance energy transfer. Transient expression studies showed the Leu723Arg variant was normally expressed but resulted in a significantly lower EC50 for extracellular calcium activation of G11 but not other G proteins (ie, Gi, Gq, Gs). The Leu723Arg substitution has a novel GOF phenotype that leads to biased CaSR activation of G11 signaling, suggesting that residue 723 specifies activation of G11 but not other G proteins. Similar studies of a previously described CaSR variant associated with hypoparathyroidism and short stature, Leu616Val, showed no changes in any G protein pathways, indicating it is likely to be a benign variant. Given the preferential activation of G11 by the Leu723Arg CaSR variant, we propose that the patient's short stature shares a similar basis to that in patients with ADH2 due to GOF variants in GNA11.
常染色体显性低钙血症（ADH）是由钙敏感受体（CASR）基因（ADH1）或编码Gα11的GNA11基因（ADH2）中的杂合功能获得性（GOF）变异导致钙依赖性信号增强引起的。ADH1和ADH2均与低钙血症以及循环中甲状旁腺激素（PTH）水平正常或异常降低有关。ADH1患者通常表现为高钙尿症，而ADH2在约42%的病例中与身材矮小有关。我们评估了一名患有甲状旁腺功能减退和身材矮小的10岁男孩。生化分析显示低钙血症、高磷血症和不一致的高钙尿症。基因分析发现CASR基因中有一个新发的杂合p.Leu723Arg变异。我们在HEK293细胞中对重组野生型和Leu723Arg钙敏感受体（CaSR）蛋白的表达进行了表征，并使用生物发光共振能量转移在体外评估了CaSR对G蛋白的激活。瞬时表达研究表明，Leu723Arg变异体正常表达，但导致G11而非其他G蛋白（即Gi、Gq、Gs）的细胞外钙激活的半数有效浓度（EC50）显著降低。Leu723Arg替代具有一种新的GOF表型，导致对G11信号的偏向性CaSR激活，表明723位残基决定了G11而非其他G蛋白的激活。对先前描述的与甲状旁腺功能减退和身材矮小相关的CaSR变异体Leu616Val的类似研究表明，任何G蛋白途径均无变化，表明它可能是一个良性变异。鉴于Leu723Arg CaSR变异体对G11的优先激活，我们提出该患者的身材矮小与因GNA11基因中的GOF变异导致的ADH2患者具有相似的基础。
