What is it about?

ROSAH is an acronym for Retinal degeneration, Optic nerve oedema, Splenomegaly, Anhydrosis (the inability to sweat) and migraine Headache, the main clinical features of ROSAH syndrome. Only recognised as a separate disease in 2019, patients are usually diagnosed as young children with failing eyesight, who become blind when they are young adults. Nearly all the 67 patients discovered so far possess the same structural alteration in the enzyme ALPK1 in which the amino acid threonine is replaced by the amino acid methionine at one position. ROSAH syndrome was discovered so recently that it is likely to still be underdiagnosed. Spiradenoma is caused by a distinct structural change in ALPK1 in which the amino acid valine at one position is replaced by the amino acid alanine. Spiradenoma presents as a disfiguring growth, usually on the head, neck or upper body, but is sometimes converted to a fatal cancer called Spiradenocarcinoma. A third or more of Spiradenoma or Spiradenocarcinoma patients display the same valine to alanine replacement in ALPK1.

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Why is it important?

Normally, ALPK1 remains in a biologically inactive form in human cells until it is switched on by ADP-heptose, a compound produced by bacteria, which is not made by human cells. Activation by ADP-heptose enables ALPK1 to trigger a series of chemical events leading to the production of substances to combat the bacterial infection. We found that the structural changes in ALPK1 causing ROSAH syndrome or Spiradenoma do not affect activation by ADP-heptose, but additionally cause it to be activated by several other molecules related to ADP-heptose, that are produced by human cells. This is important because it can explain how the abnormal forms of ALPK1 are active continuously in cells, even in the absence of any bacterial infection, leading to disease outcomes in particular human tissues.


Our findings suggest novel ways of identifying compounds that selectively inhibit the mutant, disease-causing forms of ALPK1 without affecting the normal enzyme. We therefore hope that the publication of this paper will stimulate other researchers and companies to develop drugs that will prevent blindness in children with ROSAH syndrome and deaths from spiradenocarcinoma.

Tom Snelling
University of Dundee

Read the Original

This page is a summary of: ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars, Proceedings of the National Academy of Sciences, December 2023, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2313148120.
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