Novel integrin-dependent platelet malfunction in siblings with leukocyte adhesion deficiency-III (LAD-III) caused by a point mutation in FERMT3

Kerstin Jurk; Ansgar S. Schulz; Beate E. Kehrel; Daniel Räpple; Harald Schulze; Dieter Möbest; Wilhelm W. Friedrich; Heymut Omran; Erika Deak; Reinhard Henschler; Jürgen S. Scheele; Barbara Zieger

doi:10.1160/TH09-10-0689

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 103(05): 1053-1064
DOI: 10.1160/TH09-10-0689

Platelets and Blood Cells

Schattauer GmbH

Novel integrin-dependent platelet malfunction in siblings with leukocyte adhesion deficiency-III (LAD-III) caused by a point mutation in FERMT3

Kerstin Jurk

¹Department of Anaesthesiology and Intensive Care, Experimental and Clinical Haemostasis, University-Hospital of Münster, Münster, Germany

,

Ansgar S. Schulz

²Department of Pediatrics and Adolescent Medicine, University Clinic of Ulm, Ulm, Germany

,

Beate E. Kehrel

¹Department of Anaesthesiology and Intensive Care, Experimental and Clinical Haemostasis, University-Hospital of Münster, Münster, Germany

,

Daniel Räpple

³Department of Medicine I, University of Freiburg, Freiburg, Germany

,

Harald Schulze

⁴Laboratory of Pediatric Molecular Biology, Department of General Pediatrics, Charité – University of Berlin, Berlin, Germany

,

Dieter Möbest

³Department of Medicine I, University of Freiburg, Freiburg, Germany

,

Wilhelm W. Friedrich

²Department of Pediatrics and Adolescent Medicine, University Clinic of Ulm, Ulm, Germany

,

Heymut Omran

⁸Department of General Pediatrics, University Hospital Muenster, Germany

,

Erika Deak

⁶Institute of Transfusion Medicine and Immune Hematology German Red Cross Blood Donor Service, Johann Wolfgang Goethe University Medical School, Frankfurt, Germany

,

Reinhard Henschler

¹Department of Anaesthesiology and Intensive Care, Experimental and Clinical Haemostasis, University-Hospital of Münster, Münster, Germany

,

Jürgen S. Scheele

³Department of Medicine I, University of Freiburg, Freiburg, Germany

⁷Department of Pharmacology, University of Freiburg, Freiburg, Germany

,

Barbara Zieger

⁵Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany

› Author Affiliations

Abstract

Summary

Leukocyte adhesion deficiency-III (LAD-III) also called leukocyte adhesion deficiency-1/variant (LAD1v) is a rare congenital disease caused by defective integrin activation of leukocytes and platelets. Patients with LAD-III present with non-purulent infections and increased bleeding symptoms. We report on a novel integrin-dependent platelet dys-function in two brothers with LAD-III syndrome caused by a homozygous mutation 1717C>T in the FERMT3 gene leading to a premature stop codon R573X in the focal adhesion protein kindlin-3. Stimulation of patients´ platelets with all used agonists resulted in a severely decreased binding of soluble fibrinogen indicating a defect in inside-out activation of the integrin α_IIbβ₃ (GPIIb/IIIa). Patients´ platelets did not respond to the α₂β₁-integrin agonist aggretin-A at all. Our data on granula secretion indicate for the first time that the thrombin receptor PAR-4 but not PAR-1 may be important in integrin-triggered granule secretion in response to thrombin. In contrast, collagen mediated platelet granule secretion was not affected in LAD-III-patients. Thus, integrin-signalling may be not essential in collagen-induced granule secretion. The patients’ peripheral blood mononuclear cells showed a severe loss of adhesion capacity to VCAM-1 and to endothelial cells compared to cells from healthy donors. Rap-1 activation after PMA stimulation could be observed in controls´ but not in patients´ cells. After haematogenesis stem cell transplantation (HSCT) the brothers showed no symptoms of bleeding or immunodeficiency and the integrin-dependent platelet and leukocyte functions normalised.

Keywords

Leukocyte adhesion deficiency - platelets - integrin - kindlin-3

Full Text

References

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