title: Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation.
abstract: Integrins are the major adhesion receptors of leukocytes and platelets. Beta1 and beta2 integrin function on leukocytes is crucial for a successful immune response and the platelet integrin alpha(IIb)beta3 initiates the process of blood clotting through binding fibrinogen. Integrins on circulating cells bind poorly to their ligands but become active after 'inside-out' signaling through other membrane receptors. Subjects with leukocyte adhesion deficiency-1 (LAD-I) do not express beta2 integrins because of mutations in the gene specifying the beta2 subunit, and they suffer recurrent bacterial infections. Mutations affecting alpha(IIb)beta3 integrin cause the bleeding disorder termed Glanzmann's thrombasthenia. Subjects with LAD-III show symptoms of both LAD-I and Glanzmann's thrombasthenia. Their hematopoietically-derived cells express beta1, beta2 and beta3 integrins, but defective inside-out signaling causes immune deficiency and bleeding problems. The LAD-III lesion has been attributed to a C --> A mutation in the gene encoding calcium and diacylglycerol guanine nucleotide exchange factor (CALDAGGEF1; official symbol RASGRP2) specifying the CALDAG-GEF1 protein, but we show that this change is not responsible for the LAD-III disorder. Instead, we identify mutations in the KINDLIN3 (official symbol FERMT3) gene specifying the KINDLIN-3 protein as the cause of LAD-III in Maltese and Turkish subjects. Two independent mutations result in decreased KINDLIN3 messenger RNA levels and loss of protein expression. Notably, transfection of the subjects' lymphocytes with KINDLIN3 complementary DNA but not CALDAGGEF1 cDNA reverses the LAD-III defect, restoring integrin-mediated adhesion and migration.
authors.affiliation: Leukocyte Adhesion Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Lena
authors.initials: L
authors.lastname: Svensson
authors.forename: Kimberley
authors.initials: K
authors.lastname: Howarth
authors.forename: Alison
authors.initials: A
authors.lastname: McDowall
authors.forename: Irene
authors.initials: I
authors.lastname: Patzak
authors.forename: Rachel
authors.initials: R
authors.lastname: Evans
authors.forename: Siegfried
authors.initials: S
authors.lastname: Ussar
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.forename: Ayse
authors.initials: A
authors.lastname: Metin
authors.forename: Mike
authors.initials: M
authors.lastname: Fried
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.forename: Nancy
authors.initials: N
authors.lastname: Hogg
mesh_terms: D001483:Base Sequence; D018821:CD18 Antigens / Q000378:metabolism*; D006801:Humans; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018821:CD18 Antigens; C477322:FERMT3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger