Abstract
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.