Letter abstract
Nature Medicine 15, 306 - 312 (2009)
Published online: 22 February 2009 | doi:10.1038/nm.1931
Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation
Lena Svensson1,6, Kimberley Howarth2,6, Alison McDowall1, Irene Patzak1, Rachel Evans1, Siegfried Ussar3, Markus Moser3, Ayse Metin4, Mike Fried5, Ian Tomlinson2 & Nancy Hogg1
Integrins are the major adhesion receptors of leukocytes and platelets. 
1 and 2 integrin function on leukocytes is crucial for a successful immune response and the platelet integrin 
IIb3 initiates the process of blood clotting through binding fibrinogen1, 2, 3. Integrins on circulating cells bind poorly to their ligands but become active after 'inside-out' signaling through other membrane receptors4, 5. Subjects with leukocyte adhesion deficiency-1 (LAD-I) do not express 2 integrins because of mutations in the gene specifying the 2 subunit, and they suffer recurrent bacterial infections6, 7. Mutations affecting IIb3 integrin cause the bleeding disorder termed Glanzmann's thrombasthenia3. Subjects with LAD-III show symptoms of both LAD-I and Glanzmann's thrombasthenia. Their hematopoietically-derived cells express 1, 2 and 3 integrins, but defective inside-out signaling causes immune deficiency and bleeding problems8. 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 protein9, 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.
- Leukocyte Adhesion Laboratory, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
- Molecular and Population Genetics Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
- Department of Molecular Medicine, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
- Division of Immunology, SB Ankara Diskapi Children's Hospital, 06110 Ankara, Turkey.
- University of California–San Francisco Cancer Research Institute, 2340 Sutter Street, San Francisco, California 94115, USA.
- These authors contributed equally to this work.
Correspondence to: Nancy Hogg1 e-mail: nancy.hogg@cancer.org.uk
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