Alvarez-Hernández D, Santamaría I, Rodríguez-García M, Iglesias P, Delgado-Lillo R, Cannata-Andía J B
Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación, Hospital Universitario Central de Asturias, c/Julián Clavería s/n, 33006 Oviedo, Spain.
J Mol Endocrinol. 2003 Oct;31(2):255-62. doi: 10.1677/jme.0.0310255.
A novel missense activating mutation in the extracellular calcium-sensing receptor (CaSR) is reported in this work. It was identified in three related subjects with the phenotypic features of autosomal dominant hypocalcemia (ADH). The proband, a 27-year-old woman, diagnosed as having hypoparathyroidism at 7 years of age and a history of seizures, showed the highest penetrance of the mutation. The remaining two affected members presented asymptomatic chronic hypocalcemia despite severe hypoparathyroidism associated with high levels of serum phosphate and calcium urinary excretion. The missense mutation (Glu(604)Lys) affected an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular amino-terminal domain, which seems to be required for the coupling of ligand binding to the activation of intracellular signaling pathways. This genetic change cosegregated with hypocalcemia in all the individuals where the mutation was found. As parathyroid hormone (PTH) secretion is the regulatory target of the CaSR, polymorphism analysis of the PTH gene was carried out. PTH polymorphisms were analyzed in the kindred studied. Affected members for the Glu(604)Lys CaSR mutation which also carried the uncommon PTH alleles showed higher penetrance of the mutation, with more severe autosomal dominant hypocalcemia. These results suggested that the PTH gene could act as a modifier locus of ADH, affecting the penetrance of the activating CaSR mutation described.
本研究报道了细胞外钙敏感受体（CaSR）中一种新的错义激活突变。该突变在三名具有常染色体显性低钙血症（ADH）表型特征的相关受试者中被发现。先证者为一名27岁女性，7岁时被诊断为甲状旁腺功能减退且有癫痫病史，该突变在她身上的外显率最高。其余两名受影响成员尽管患有严重的甲状旁腺功能减退，伴有高血清磷水平和高钙尿排泄，但表现为无症状性慢性低钙血症。错义突变（Glu(604)Lys）影响了细胞外氨基末端富含半胱氨酸结构域C末端的一个氨基酸残基，该残基似乎是配体结合与细胞内信号通路激活偶联所必需的。在所有发现该突变的个体中，这种基因变化与低钙血症共分离。由于甲状旁腺激素（PTH）分泌是CaSR的调节靶点，因此对PTH基因进行了多态性分析。在研究的家系中分析了PTH多态性。携带不常见PTH等位基因的Glu(604)Lys CaSR突变的受影响成员，其突变外显率更高，常染色体显性低钙血症更严重。这些结果表明，PTH基因可能作为ADH的修饰位点，影响所描述的激活CaSR突变的外显率。
