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.

Loss of kindlin-3 alters the threshold for NK cell activation in human leukocyte adhesion deficiency-III

“…[12][13][14][15][16][17][18] Experiments performed on cells derived from LAD-III-deficient patients determined that kindlin-3 is essential for integrin activation in different cells. 9,[13][14][15][16]39 Kindlin-3 deficiency resulted in impairment of many integrin activities, including adhesion, spreading, aggregation, and migration.…”

“…11 The importance of kindlin-3 in integrin activity was demonstrated most noticeably through the recent identification of patients with leukocyte adhesion deficiency (LAD) type III. [12][13][14][15][16][17][18] These patients have recurrent clinical bleeding and infections few days after birth. [13][14][15][16][17][18][19] The disease is very rare, and only a few cases were described so far.…”

“…[12][13][14][15][16][17][18] These patients have recurrent clinical bleeding and infections few days after birth. [13][14][15][16][17][18][19] The disease is very rare, and only a few cases were described so far. 16,18,20 Studies performed on platelets, lymphocytes, and PMNs derived from patients demonstrated that loss of kindlin-3 affects integrin activation in all cell types studied.…”

“…16,18,20 Studies performed on platelets, lymphocytes, and PMNs derived from patients demonstrated that loss of kindlin-3 affects integrin activation in all cell types studied. [13][14][15][16][17][18][19] Natural killer (NK) cells kill virus-infected cells, bacteria, and tumor cells without prior activation, 21 although recent data demonstrated that NK cells could possess a certain type of memory. 22,23 NK cell activity results from a balance between activating and inhibitory signals.…”

Leukocyte Beta2-Integrins; Genes and Disease

“…In this disorder, the patients display similar symptoms to patients with LAD-I, but also present with a Glanzmann-type bleeding disorder and in some cases also with osteopetrosis [27][28][29][30]. The causative mutations were found to occur in the FERMT3 gene that encodes kindlin-3, introducing premature stop codons resulting in a non-functioning protein [31][32][33][34][35][36]. Kindlin-3 is one of three orthologs found in humans and has been shown to bind to and regulate beta1-, beta2-and beta3-integrin functions [37].…”