Oculocerebrorenal syndrome of Lowe protein controls cytoskeletal reorganisation during human platelet spreading.

Abstract

Lowe syndrome (LS) is a rare, X-linked disorder characterised by numerous symptoms affecting the brain, the eyes, and the kidneys. It is caused by mutations in the oculocerebrorenal syndrome of Lowe (OCRL) protein, a 5-phosphatase localised in different cellular compartments that dephosphorylates phosphatidylinositol-4,5-bisphosphate into phosphatidylinositol-4-monophosphate. Some patients with LS also have bleeding disorders, with normal to low platelet (PLT) count and impaired PLT function. However, the mechanism of PLT dysfunction in patients with LS is not completely understood. The main function of PLTs is to activate upon vessel wall injury and stop the bleeding by clot formation. PLT activation is accompanied by a shape change that is a result of massive cytoskeletal rearrangements. Here, we show that OCRL-inhibited human PLTs do not fully spread, form mostly filopodia, and accumulate actin nodules. These nodules co-localise with ARP2/3 subunit p34, vinculin, and sorting nexin 9. Furthermore, OCRL-inhibited PLTs have a retained microtubular coil with high levels of acetylated tubulin. Also, myosin light chain phosphorylation is decreased upon OCRL inhibition, without impaired degranulation or integrin activation. Taken together, these results suggest that OCRL contributes to cytoskeletal rearrangements during PLT activation that could explain mild bleeding problems in patients with LS.

• Authors: Ana Bura, Maria Antonietta de Matteis, Markus Bender, Maurice Swinkels, Jurjen Versluis, A J Gerard Jansen, Antonija Jurak Begonja
• Journal: British journal of haematology (Br J Haematol) Vol. 200 Issue 1 Pg. 87-99 (01 2023) ISSN: 1365-2141 [Electronic] England
• PMID: 36176266 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 British Society for Haematology and John Wiley & Sons Ltd.

Chemical References

• Actins

Topics

• Humans
• Oculocerebrorenal Syndrome (genetics)
• Actins
• Kidney (metabolism)
• WAGR Syndrome
• Mutation