FERMT3 blocking peptide

Leukocyte adhesion deficiency (LAD) is an immunodeficiency caused by defects in the adhesion of leukocytes (especially neutrophils) to the blood vessel wall. As a result, patients with LAD suffer from severe bacterial infections and impaired wound healing, accompanied by neutrophilia. In LAD-I, mutations are found in ITGB2, the gene that encodes the beta subunit of the beta(2) integrins. This syndrome is characterized directly after birth by delayed separation of the umbilical cord. In the rare LAD-II disease, the fucosylation of selectin ligands is disturbed, caused by mutations in SLC35C1, the gene that encodes a GDP-fucose transporter of the Golgi system. LAD-II patients lack the H and Lewis Le(a) and Le(b) blood group antigens. Finally, in LAD-III (also called LAD-I/variant) the conformational activation of the hematopoietically expressed beta integrins is disturbed, leading to leukocyte and platelet dysfunction. This last syndrome is caused by mutations in FERMT3, encoding the kindlin-3 protein in all blood cells that is involved in the regulation of beta integrin conformation. (C) 2011 Elsevier Inc. All rights reserved.

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.