Diabetes With Multiple Autoimmune and Inflammatory Conditions Linked to an Activating SKAP2 Mutation
Diabetes With Multiple Autoimmune and Inflammatory Conditions Linked to an Activating SKAP2 Mutation
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DOI：
10.2337/dc20-2317
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发表时间：
2021-08-01
期刊：
影响因子：
16.2
通讯作者：
Lowell, Clifford A.
中科院分区：
文献类型：
--
作者：
Rutsch, Niklas;Chamberlain, Chester E.;Lowell, Clifford A.
多个全基因组关联研究已经确定了SKAP 2基因座与1型糖尿病（T1D）之间的强烈遗传连锁，但这如何导致疾病仍然不清楚。在这里，我们描述了T1D患者中新型SKAP 2编码突变的功能后果，以进一步了解这如何影响免疫耐受。研究设计和方法我们确定了一个24岁的T1D和其他自身免疫性和炎症性疾病的个体。先证者和一级亲属被招募进行全外显子组测序。使用细胞系和从家族成员收集的原代骨髓免疫细胞进行蛋白质变体的功能研究。结果测序结果证实先证者SKAP 2基因存在一个新的突变体（c.457G> A，p.Gly153Arg）。使用来自个体的单核细胞衍生的巨噬细胞的测定揭示了整合素途径的增强活性和在不存在趋化因子刺激的情况下的迁移表型，这与SKAP 2 p.Gly153Arg具有组成性活性一致。P.Gly153Arg变异体位于保守的脂质结合环中，在人巨噬细胞系中表达时诱导相似的表型。SKAP2 p.Gly153Arg是一种功能获得性致病突变，可破坏骨髓免疫细胞功能，可能导致免疫耐受和T1D的中断。结论SKAP 2在髓系细胞活化和迁移中起关键作用。在患有T1D和多种自身免疫性疾病的患者中的这种特定突变暗示了在自身免疫性T1D中激活SKAP 2变体的作用。
OBJECTIVE Multiple genome-wide association studies have identified a strong genetic linkage between the SKAP2 locus and type 1 diabetes (T1D), but how this leads to disease remains obscure. Here, we characterized the functional consequence of a novel SKAP2 coding mutation in a patient with T1D to gain further insight into how this impacts immune tolerance. RESEARCH DESIGN AND METHODS We identified a 24-year-old individual with T1D and other autoimmune and inflammatory conditions. The proband and first-degree relatives were recruited for whole-exome sequencing. Functional studies of the protein variant were performed using a cell line and primary myeloid immune cells collected from family members. RESULTS Sequencing identified a de novo SKAP2 variant (c.457G>A, p.Gly153Arg) in the proband. Assays using monocyte-derived macrophages from the individual revealed enhanced activity of integrin pathways and a migratory phenotype in the absence of chemokine stimulation, consistent with SKAP2 p.Gly153Arg being constitutively active. The p.Gly153Arg variant, located in the well-conserved lipid-binding loop, induced similar phenotypes when expressed in a human macrophage cell line. SKAP2 p.Gly153Arg is a gain-of-function, pathogenic mutation that disrupts myeloid immune cell function, likely resulting in a break in immune tolerance and T1D. CONCLUSIONS SKAP2 plays a key role in myeloid cell activation and migration. This particular mutation in a patient with T1D and multiple autoimmune conditions implicates a role for activating SKAP2 variants in autoimmune T1D.