title: Novel integrin-dependent platelet malfunction in siblings with leukocyte adhesion deficiency-III (LAD-III) caused by a point mutation in FERMT3.
abstract: 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 dysfunction 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 alpha(IIb) beta(3) (GPIIb/IIIa). Patients platelets did not respond to the alpha(2)beta(1)-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.
authors.affiliation: Department of Anaesthesiology and Intensive Care, Experimental and Clinical Haemostasis, University-Hospital of Münster, Münster, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Jurk
authors.forename: Ansgar S
authors.initials: AS
authors.lastname: Schulz
authors.forename: Beate E
authors.initials: BE
authors.lastname: Kehrel
authors.forename: Daniel
authors.initials: D
authors.lastname: Räpple
authors.forename: Harald
authors.initials: H
authors.lastname: Schulze
authors.forename: Dieter
authors.initials: D
authors.lastname: Möbest
authors.forename: Wilhelm W
authors.initials: WW
authors.lastname: Friedrich
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.forename: Erika
authors.initials: E
authors.lastname: Deak
authors.forename: Reinhard
authors.initials: R
authors.lastname: Henschler
authors.forename: Jürgen S
authors.initials: JS
authors.lastname: Scheele
authors.forename: Barbara
authors.initials: B
authors.lastname: Zieger
mesh_terms: D002448:Cell Adhesion / Q000235:genetics; D015550:Cell Degranulation / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D046528:Chimerism; D003094:Collagen / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006470:Hemorrhage; D006801:Humans; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000097:blood* / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D015539:Platelet Activation / Q000235:genetics; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C477322:FERMT3 protein, human; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; C484658:RAP1GAP protein, human; D019010:Vascular Cell Adhesion Molecule-1; C032193:glycoprotein receptor GPIb-IX; D003094:Collagen; D013917:Thrombin