Role of oculocerebrorenal syndrome of Lowe (OCRL) protein in megakaryocyte maturation, platelet production and functions: a study in patients with Lowe syndrome

Br J Haematol. 2021 Mar;192(5):909-921. doi: 10.1111/bjh.17346. Epub 2021 Feb 2.


Lowe syndrome (LS) is an oculocerebrorenal syndrome of Lowe (OCRL1) genetic disorder resulting in a defect of the OCRL protein, a phosphatidylinositol-4,5-bisphosphate 5-phosphatase containing various domains including a Rho GTPase-activating protein (RhoGAP) homology domain catalytically inactive. We previously reported surgery-associated bleeding in patients with LS, suggestive of platelet dysfunction, accompanied with a mild thrombocytopenia in several patients. To decipher the role of OCRL in platelet functions and in megakaryocyte (MK) maturation, we conducted a case-control study on 15 patients with LS (NCT01314560). While all had a drastically reduced expression of OCRL, this deficiency did not affect platelet aggregability, but resulted in delayed thrombus formation on collagen under flow conditions, defective platelet spreading on fibrinogen and impaired clot retraction. We evidenced alterations of the myosin light chain phosphorylation (P-MLC), with defective Rac1 activity and, inversely, elevated active RhoA. Altered cytoskeleton dynamics was also observed in cultured patient MKs showing deficient proplatelet extension with increased P-MLC that was confirmed using control MKs transfected with OCRL-specific small interfering(si)RNA (siOCRL). Patients with LS also had an increased proportion of circulating barbell-shaped proplatelets. Our present study establishes that a deficiency of the OCRL protein results in a defective actomyosin cytoskeleton reorganisation in both MKs and platelets, altering both thrombopoiesis and some platelet responses to activation necessary to ensure haemostasis.

Keywords: Lowe syndrome; OCRL; RhoGAP; megakaryocytes; myosin light chain; platelet functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actomyosin / analysis
  • Adolescent
  • Adult
  • Anemia / etiology
  • Blood Coagulation
  • Blood Platelets / cytology*
  • Blood Platelets / ultrastructure
  • Case-Control Studies
  • Cell Shape
  • Child
  • Collagen
  • Cytoskeleton / ultrastructure
  • Female
  • Gene Silencing
  • Humans
  • Male
  • Megakaryocytes / cytology*
  • Megakaryocytes / ultrastructure
  • Middle Aged
  • Mutation
  • Myosin Light Chains / metabolism
  • Oculocerebrorenal Syndrome / blood
  • Oculocerebrorenal Syndrome / genetics*
  • Oculocerebrorenal Syndrome / pathology
  • Phosphoric Monoester Hydrolases / deficiency
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / physiology*
  • Phosphorylation
  • Protein Domains
  • Protein Processing, Post-Translational
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Thrombocytopenia / etiology
  • Thrombopoiesis / physiology*
  • Young Adult


  • Myosin Light Chains
  • RNA, Small Interfering
  • Collagen
  • Actomyosin
  • Phosphoric Monoester Hydrolases
  • OCRL protein, human

Associated data