Snelling Tom, Garnotel Leo O, Jeru Isabelle, Tusseau Maud, Cuisset Laurence, Perlat Antoinette, Minard Geoffrey, Benquey Thibaut, Maucourant Yann, Wood Nicola T, Cohen Philip, Ziegler Alban
MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Department of Ophthalmology, University Hospital of Reims, Reims, France.
Open Biol. 2024 Dec;14(12):240260. doi: 10.1098/rsob.240260. Epub 2024 Dec 4.
Retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and migraine headache (ROSAH) syndrome is an autosomal dominant disorder and to date is known to be caused by either the Thr237Met or Tyr254Cys variant in the protein kinase ALPK1. Here, we identify a family in which ROSAH syndrome is caused by a novel variant in which Ser277 is changed to Phe. All six patients examined display ocular inflammation and optic nerve elevation, four have retinal degeneration and four are registered blind. In contrast to wild-type ALPK1, which is activated specifically by bacterial ADP-heptose, ALPK1[Ser277Phe] is also activated by the human metabolites UDP-mannose and ADP-ribose and more strongly than the most frequent ROSAH-causing variant (ALPK1[Thr237Met]) but, unlike ALPK1[Thr237Met], ALPK1[Ser277Phe] is also activated by GDP-mannose. These observations can explain why ALPK1 variants causing ROSAH syndrome display constitutive activity in human cells. The side chains of Ser277 and Tyr254 interact in the crystal structure of ALPK1, but mutational analysis established that it is not the loss of this hydrogen bond between Ser277 and Tyr254 that alters the specificity of the ADP-heptose-binding pocket in the Ser277Phe and Tyr254Cys variants. The characterization of ALPK1 variants that cause ROSAH syndrome suggests ways in which drugs that selectively inhibit these disease-causing variants may be developed.
视网膜营养不良、视神经水肿、脾肿大、无汗和偏头痛（ROSAH）综合征是一种常染色体显性疾病，迄今为止已知由蛋白激酶ALPK1中的Thr237Met或Tyr254Cys变体引起。在此，我们鉴定出一个家族，其中ROSAH综合征由一种新变体引起，即Ser277变为Phe。所检查的所有6名患者均表现出眼部炎症和视神经隆起，4人有视网膜变性，4人登记为失明。与野生型ALPK1不同，野生型ALPK1仅由细菌ADP-庚糖特异性激活，而ALPK1[Ser277Phe]也可被人类代谢产物UDP-甘露糖和ADP-核糖激活，且比最常见的导致ROSAH的变体（ALPK1[Thr237Met]）激活作用更强，但与ALPK1[Thr237Met]不同的是，ALPK1[Ser277Phe]也可被GDP-甘露糖激活。这些观察结果可以解释为什么导致ROSAH综合征的ALPK1变体在人类细胞中表现出组成型活性。Ser277和Tyr254的侧链在ALPK1的晶体结构中相互作用，但突变分析表明，并非Ser277和Tyr254之间氢键的丧失改变了Ser277Phe和Tyr254Cys变体中ADP-庚糖结合口袋的特异性。对导致ROSAH综合征的ALPK1变体的表征为开发选择性抑制这些致病变体的药物提供了思路。
