A novel mutation in the calcium-sensing receptor responsible for autosomal dominant hypocalcemia in a family with two uncommon parathyroid hormone polymorphisms
A novel mutation in the calcium-sensing receptor responsible for autosomal dominant hypocalcemia in a family with two uncommon parathyroid hormone polymorphisms
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DOI：
10.1677/jme.0.0310255
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发表时间：
2003-10-01
影响因子：
3.5
通讯作者：
Cannata-Andía, JB
中科院分区：
文献类型：
--
作者：
Alvarez-Hernández, D;Santamaría, I;Cannata-Andía, JB
本文报道了一种新的细胞外钙敏感受体（CaSR）的错义激活突变。它被确定在三个相关的主题与常染色体显性遗传性低钙血症（ADH）的表型特征。先证者是一名27岁的女性，7岁时被诊断为甲状旁腺功能减退症，有癫痫发作史，表现出最高的突变率。其余两名受影响的成员提出了无症状的慢性低钙血症，尽管严重的甲状旁腺功能低下与高水平的血清磷和尿钙排泄。错义突变（Glu（604）Lys）影响胞外氨基末端结构域的富含半胱氨酸结构域的C末端中的氨基酸残基，这似乎是配体结合与胞内信号传导途径的活化的偶联所需的。由于甲状旁腺激素（PTH）的分泌是CaSR的调控靶点，因此我们对PTH基因进行了多态性分析。PTH多态性进行了分析的亲属研究。Glu（604）LysCaSR突变的受影响成员也携带罕见的PTH等位基因，其突变率较高，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突变的频率。
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.