大规模外显子组数据集揭示了一类新的衔接蛋白相关蛋白复合物 2 西格玛亚基（AP2σ）突变，这些突变位于与 AP2α亚基的界面上，会损害钙敏感受体信号转导。
Large-scale exome datasets reveal a new class of adaptor-related protein complex 2 sigma subunit (AP2σ) mutations, located at the interface with the AP2 alpha subunit, that impair calcium-sensing receptor signalling.
机构信息
Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford OX3 7LJ, UK.
Geisinger Clinic, Weis Center for Research, Danville, PA 17822, USA.
出版信息
Hum Mol Genet. 2018 Mar 1;27(5):901-911. doi: 10.1093/hmg/ddy010.
Mutations of the sigma subunit of the heterotetrameric adaptor-related protein complex 2 (AP2σ) impair signalling of the calcium-sensing receptor (CaSR), and cause familial hypocalciuric hypercalcaemia type 3 (FHH3). To date, FHH3-associated AP2σ mutations have only been identified at one residue, Arg15. We hypothesized that additional rare AP2σ variants may also be associated with altered CaSR function and hypercalcaemia, and sought for these by analysing >111 995 exomes (>60 706 from ExAc and dbSNP, and 51 289 from the Geisinger Health System-Regeneron DiscovEHR dataset, which also contains clinical data). This identified 11 individuals to have 9 non-synonymous AP2σ variants (Arg3His, Arg15His (x3), Ala44Thr, Phe52Tyr, Arg61His, Thr112Met, Met117Ile, Glu122Gly and Glu142Lys) with 3 of the 4 individuals who had Arg15His and Met117Ile AP2σ variants having mild hypercalcaemia, thereby indicating a prevalence of FHH3-associated AP2σ mutations of ∼7.8 per 100 000 individuals. Structural modelling of the novel eight AP2σ variants (Arg3His, Ala44Thr, Phe52Tyr, Arg61His, Thr112Met, Met117Ile, Glu122Gly and Glu142Lys) predicted that the Arg3His, Thr112Met, Glu122Gly and Glu142Lys AP2σ variants would disrupt polar contacts within the AP2σ subunit or affect the interface between the AP2σ and AP2α subunits. Functional analyses of all eight AP2σ variants in CaSR-expressing cells demonstrated that the Thr112Met, Met117Ile and Glu142Lys variants, located in the AP2σ α4-α5 helical region that forms an interface with AP2α, impaired CaSR-mediated intracellular calcium (Cai2+) signalling, consistent with a loss of function, and this was rectified by treatment with the CaSR positive allosteric modulator cinacalcet. Thus, our studies demonstrate another potential class of FHH3-causing AP2σ mutations located at the AP2σ-AP2α interface.
AP2 异源三聚体衔接相关蛋白复合物 2（AP2σ）的σ亚基突变会损害钙敏感受体（CaSR）的信号转导，并导致家族性低钙性高钙血症 3 型（FHH3）。迄今为止，仅在一个残基（精氨酸 15）发现了与 FHH3 相关的 AP2σ 突变。我们假设，其他罕见的 AP2σ 变体也可能与 CaSR 功能改变和高钙血症有关，为此，我们分析了超过 111995 个外显子（来自 ExAc 和 dbSNP 的超过 60706 个，来自 Geisinger Health System-Regeneron DiscovEHR 数据集的 51289 个，该数据集还包含临床数据）。这鉴定出 11 个人有 9 种非同义 AP2σ 变体（精氨酸 3 到组氨酸，精氨酸 15 到组氨酸（x3），丙氨酸 44 到苏氨酸，苯丙氨酸 52 到酪氨酸，精氨酸 61 到组氨酸，苏氨酸 112 到蛋氨酸，蛋氨酸 117 到异亮氨酸，谷氨酸 122 到甘氨酸和谷氨酸 142 到赖氨酸），其中 4 个人中有 3 个人有精氨酸 15 到组氨酸和蛋氨酸 117 到异亮氨酸的 AP2σ 变体，伴有轻度高钙血症，因此表明 FHH3 相关的 AP2σ 突变的患病率约为每 10 万人中有 7.8 个。对新的 8 种 AP2σ 变体（精氨酸 3 到组氨酸，丙氨酸 44 到苏氨酸，苯丙氨酸 52 到酪氨酸，精氨酸 61 到组氨酸，苏氨酸 112 到蛋氨酸，蛋氨酸 117 到异亮氨酸，谷氨酸 122 到甘氨酸和谷氨酸 142 到赖氨酸）的结构建模预测，精氨酸 3 到组氨酸、苏氨酸 112 到蛋氨酸、谷氨酸 122 到甘氨酸和谷氨酸 142 到赖氨酸的 AP2σ 变体将破坏 AP2σ 亚基内的极性接触，或影响 AP2σ 与 AP2α 亚基之间的界面。在表达 CaSR 的细胞中对所有 8 种 AP2σ 变体进行的功能分析表明，位于与 AP2α 形成界面的 AP2σα4-α5 螺旋区的苏氨酸 112 到蛋氨酸、蛋氨酸 117 到异亮氨酸和谷氨酸 142 到赖氨酸变体，损害了 CaSR 介导的细胞内钙（Cai2+）信号转导，与功能丧失一致，而用 CaSR 正变构调节剂西那卡塞治疗可以纠正这种情况。因此，我们的研究表明，另一种潜在的 FHH3 致病 AP2σ 突变位于 AP2σ-AP2α 界面。
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