Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia.
Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia.
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DOI：
10.1056/nejmoa1300253
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发表时间：
2013-06-27
期刊：
影响因子：
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通讯作者：
Thakker RV
中科院分区：
文献类型：
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作者：
Nesbit MA;Hannan FM;Howles SA;Babinsky VN;Head RA;Cranston T;Rust N;Hobbs MR;Heath H 3rd;Thakker RV
家族性低钙尿性高钙血症是一种遗传异质性疾病，有三种变异类型：1型、2型和3型。1型是由于钙敏感受体功能缺失突变所致，钙敏感受体是一种鸟嘌呤核苷酸结合蛋白(G蛋白)偶联受体，通过G蛋白亚单位α11(Gα11)传递信号。3型与适配器相关蛋白复合体2，Sigma 1亚单位(AP2S1)突变有关，AP2S1突变导致钙敏感受体内吞改变。我们推测2型是由于Gα11基因突变导致Gα11功能丧失所致，因为G GNA11参与钙敏感受体信号转导，并且其基因(GNA11)和2型基因共定位在染色体19p13.3上。我们还推测，影响Gα11功能获得的突变，如影响钙敏感受体功能获得的突变，导致常染色体显性遗传性1型低钙血症，可能导致低钙血症。我们对一个家族性2型低钙尿性高钙血症患者和9例家族性低钙尿性高钙血症患者进行了GNA11突变分析，这些患者编码钙敏感受体(CaSR)或AP2S1的基因没有突变。我们还对8名没有CaSR突变的无血缘关系的低钙血症患者进行了这项分析。此外，我们还研究了GNA11突变对人胚胎肾293细胞Gα11蛋白结构和钙敏感受体信号转导的影响。家族性低钙尿性高钙血症2型家系中有一个保守的Gα11异亮氨酸(Ile200del)框内缺失，9例无血缘关系的家族性低钙尿性高钙血症患者中有1例有错义突变(Leu135Gln)。在两名无关的低钙血症患者中检测到错义GNA11突变(Arg181Gln和Phe341Leu)，因此他们被确认为常染色体显性2型低血钙症。所有四个GNA11突变都预示着蛋白质结构的破坏，基于体外表达的评估显示，家族性低钙尿性高钙血症2型相关突变降低了表达钙敏感受体的细胞对细胞外钙浓度变化的敏感性，而常染色体显性显性低钙血症2型相关突变增加了细胞的敏感性。功能丧失的Gα11突变导致家族性2型低钙尿性高钙血症，功能获得的Gα11突变导致一种被指定为常染色体显性遗传性低钙血症2型的临床疾病。(由英国医学研究委员会和其他机构资助。)
Familial hypocalciuric hypercalcemia is a genetically heterogeneous disorder with three variants: types 1, 2, and 3. Type 1 is due to loss-of-function mutations of the calcium-sensing receptor, a guanine nucleotide–binding protein (G-protein)–coupled receptor that signals through the G-protein subunit α11 (Gα11). Type 3 is associated with adaptor-related protein complex 2, sigma 1 subunit (AP2S1) mutations, which result in altered calcium-sensing receptor endocytosis. We hypothesized that type 2 is due to mutations effecting Gα11 loss of function, since Gα11 is involved in calcium-sensing receptor signaling, and its gene (GNA11) and the type 2 locus are colocalized on chromosome 19p13.3. We also postulated that mutations effecting Gα11 gain of function, like the mutations effecting calcium-sensing receptor gain of function that cause autosomal dominant hypocalcemia type 1, may lead to hypocalcemia. We performed GNA11 mutational analysis in a kindred with familial hypocalciuric hypercalcemia type 2 and in nine unrelated patients with familial hypocalciuric hypercalcemia who did not have mutations in the gene encoding the calcium-sensing receptor (CASR) or AP2S1. We also performed this analysis in eight unrelated patients with hypocalcemia who did not have CASR mutations. In addition, we studied the effects of GNA11 mutations on Gα11 protein structure and calcium-sensing receptor signaling in human embryonic kidney 293 (HEK293) cells. The kindred with familial hypocalciuric hypercalcemia type 2 had an in-frame deletion of a conserved Gα11 isoleucine (Ile200del), and one of the nine unrelated patients with familial hypocalciuric hypercalcemia had a missense GNA11 mutation (Leu135Gln). Missense GNA11 mutations (Arg181Gln and Phe341Leu) were detected in two unrelated patients with hypocalcemia; they were therefore identified as having autosomal dominant hypocalcemia type 2. All four GNA11 mutations predicted disrupted protein structures, and assessment on the basis of in vitro expression showed that familial hypocalciuric hypercalcemia type 2–associated mutations decreased the sensitivity of cells expressing calcium-sensing receptors to changes in extracellular calcium concentrations, whereas autosomal dominant hypocalcemia type 2–associated mutations increased cell sensitivity. Gα11 mutants with loss of function cause familial hypocalciuric hypercalcemia type 2, and Gα11 mutants with gain of function cause a clinical disorder designated as autosomal dominant hypocalcemia type 2. (Funded by the United Kingdom Medical Research Council and others.)