title: A novel leukocyte adhesion deficiency III variant: kindlin-3 deficiency results in integrin- and nonintegrin-related defects in different steps of leukocyte adhesion.
abstract: Leukocyte adhesion deficiency type III is a recently described condition involving a Glanzmann-type bleeding syndrome and leukocyte adhesion deficiency. This was ascribed to a defect of the FERMT3 gene resulting in abnormal expression of kindlin-3, a protein expressed in hematopoietic cells with a major role in the regulation of integrin activation. In this article, we describe a patient with a new mutation of FERMT3 and lack of kindlin-3 expression in platelets and leukocytes. We assayed quantitatively the first steps of kindlin-3-defective leukocyte adhesion, namely, initial bond formation, bond strengthening, and early spreading. Initial bond formation was readily stimulated with neutrophils stimulated by fMLF, and neutrophils and lymphocytes stimulated by a phorbol ester or Mn(2+). In contrast, attachment strengthening was defective in the patient's lymphocytes treated with PMA or Mn(2+), or fMLF-stimulated neutrophils. However, attachment strengthening was normal in patient's neutrophils treated with phorbol ester or Mn(2+). In addition, the patient's T lymphocytes displayed defective integrin-mediated spreading and a moderate but significant decrease of spreading on anti-CD3-coated surfaces. Patient's neutrophils displayed a drastic alteration of integrin-mediated spreading after fMLF or PMA stimulation, whereas signaling-independent Mn(2+) allowed significant spreading. In conclusion, the consequences of kindlin-3 deficiency on β(2) integrin function depend on both cell type and the stimulus used for integrin activation. Our results suggest looking for a possible kindlin-3 involvement in membrane dynamical event independent of integrin-mediated adhesion.
authors: Laboratoire d'Immunologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, 13385 Marseille Cedex 05, France.
authors: Philippe
authors: P
authors: Robert
authors: Matthias
authors: M
authors: Canault
authors: Catherine
authors: C
authors: Farnarier
authors: Alan
authors: A
authors: Nurden
authors: Charlotte
authors: C
authors: Grosdidier
authors: Vincent
authors: V
authors: Barlogis
authors: Pierre
authors: P
authors: Bongrand
authors: Anne
authors: A
authors: Pierres
authors: Hervé
authors: H
authors: Chambost
authors: Marie-Christine
authors: MC
authors: Alessi
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001792:Blood Platelets / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002469:Cell Separation; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D039421:Integrin alpha2 / Q000235:genetics; D016023:Integrins / Q000378:metabolism; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics*; D009504:Neutrophils / Q000378:metabolism*; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C477322:FERMT3 protein, human; C056564:ITGA2B protein, human; D039421:Integrin alpha2; D016023:Integrins; D008565:Membrane Proteins; D009363:Neoplasm Proteins