导致 ROSAH 综合征的新型 ALPK1 变异的发现和功能分析

Tom Snelling, Leo Olory-Garnotel, Isabella Jeru, Maud Tusseau, Laurence Cuisset, Antoinette Perlat, Geoffrey Minard, Thibaut Benquey, Yann Maucourant, Nicola T Wood, Philip Cohen, Alban Ziegler
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引用次数: 0

摘要

ROSAH 综合征是一种常染色体显性自身炎症性疾病,其特征是由蛋白激酶 ALPK1 的致病变异引起的视觉障碍。迄今为止,只有两种变异可导致 ROSAH 综合征:67 位患者中有 66 位携带 Thr237Met 变异,而一位患者携带 Tyr254Cys 变异。在这里,我们发现了一个因 ALPK1 中的 Ser277Phe 变异而导致 ROSAH 综合征的家族。该家族的表型变异性很高,7 人中有 4 人双目失明。几个家族成员出现多汗症、脾肿大和关节炎。ALPK1[Ser277Phe]在细菌感染过程中会被细菌代谢物ADP-庚糖特异性激活,与野生型ALPK1不同,ALPK1[Ser277Phe]也会被人类代谢物UDP-甘露糖和ADP-核糖激活,甚至比ALPK1[Thr237Met]变体激活得更强。然而,与 ALPK1[Thr237Met]不同,ALPK1[Ser277Phe]还能被 GDP-甘露糖激活。这些观察结果可以解释为什么这些 ALPK1 变体在没有 ADP-heptose 的情况下也能在细胞中活跃,从而解释为什么患者会出现自体炎症。对 ALPK1 三维结构的研究发现,Ser277 和 Tyr254 的侧链相互作用,但突变分析表明,这种相互作用对 ADP-庚糖结合位点的完整性并不重要。相反,用一个大的疏水性苯丙氨酸残基取代 Ser277 或用一个小得多的半胱氨酸残基取代 Tyr254 才能改变 ADP- 庚糖结合口袋的特异性。对导致 ROSAH 综合征的 ALPK1 变体的特征描述表明,有可能开发出选择性抑制这些致病变体的药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Discovery and functional analysis of a novel ALPK1 variant causing ROSAH syndrome
ROSAH syndrome is an autosomal dominant autoinflammatory disorder characterised by visual disturbance caused by pathogenic variation in the protein kinase ALPK1. Only two such variants have been reported to cause ROSAH syndrome to date: 66 out of 67 patients harbour the Thr237Met variant, while a single patient carries a Tyr254Cys variant. Here we identify a family in which ROSAH syndrome is caused by a Ser277Phe variant in ALPK1. The phenotypic variability in this family is high, with four of the seven individuals legally blind. Hypohidrosis, splenomegaly and arthritis were present in several family members. In contrast to wildtype ALPK1, which is activated specifically by the bacterial metabolite ADP-heptose during bacterial infection, ALPK1[Ser277Phe] was also activated by the human metabolites UDP-mannose and ADP-ribose, even more strongly than the ALPK1[Thr237Met] variant. However, unlike ALPK1[Thr237Met], ALPK1[Ser277Phe] could additionally be activated by GDP-mannose. These observations can explain why these ALPK1 variants are active in cells in the absence of ADP-heptose and hence why patients have episodes of autoinflammation. Examination of the three-dimensional structure of ALPK1 revealed that the sidechains of Ser277 and Tyr254 interact but mutational analysis established that this interaction is not critical for the integrity of the ADP-heptose binding site. Instead, it is the replacement of Ser277 by a large hydrophobic phenylalanine residue or the replacement of Tyr254 by a much smaller cysteine residue that is responsible for altering the specificity of the ADP-heptose-binding pocket. The characterisation of ALPK1 variants that cause ROSAH syndrome suggests ways in which drugs that inhibit these disease- causing variants selectively can be developed.
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