Background

Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin).

Objective

We sought to characterize the genetic cause and clinical spectrum of Hz/Hc.

Methods

Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA.

Results

Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p.E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 ± 1300 μg/mL) compared with those with PAPA syndrome (116 ± 74 μg/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1.

Conclusion

Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E→K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family.

中文翻译：

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单个氨基酸电荷开关定义了临床上独特的脯氨酸-丝氨酸-苏氨酸磷酸酶相互作用蛋白1（PSTPIP1）相关的炎性疾病

背景

高锌血症和高钙保护素血症（Hz / Hc）是一种独特的自身炎症实体，涉及极高的血清浓度的促炎性警报蛋白髓样相关蛋白（MRP）8/14（S100A8 / S100A9和钙卫蛋白）。

目的

我们试图表征Hz / Hc的遗传原因和临床频谱。

方法

在14例Hz / Hc患者中进行了脯氨酸-丝氨酸-苏氨酸磷酸酶相互作用蛋白1（PSTPIP1）基因测序，并将其临床表型与11例化脓性关节炎，坏疽性脓皮病和痤疮（PAPA）综合征的患者进行了临床表型比较。通过免疫沉淀和蛋白质印迹的方法分析了PSTPIP1-pyrin的相互作用。生成了PSTPIP1二聚体的结构模型。使用多重免疫分析法分析细胞因子谱，并使用ELISA分析MRP8 / 14血清浓度。

结果

13名患者因PSTPIP1基因的错义突变而杂合，导致p.E250K突变，其中1名携带了导致p.E257K的突变。两种突变均会在对蛋白质-蛋白质相互作用至关重要的区域内改变PSTPIP1二聚体模型的静电势。与患有PAPA综合征的患者（116±74μg/ mL）相比，具有Hz / Hc的患者具有极高的MRP8 / 14浓度（2045±1300μg/ mL），并且具有独特的临床表型。特定的细胞因子谱与Hz / Hc相关。Hz / Hc突变改变了PSTPIP1的蛋白质结合，通过PSTPIP1的磷酸化增加了与吡喃的相互作用。

结论

突变导致PSTPIP1的y域电荷逆转（E→K）和与吡喃的相互作用增强，导致了一种独特的自发炎性疾病，由PAPA综合征患者未发现的临床和生化特征定义，表明突变具有独特的基因型与表型相关性在PSTPIP1基因中。这是第一个先天性自体炎症综合征，其中警报是由警报蛋白家族成员的失控释放引起的。