Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med

Leukocyte Adhesion Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Nature medicine (Impact Factor: 27.36). 03/2009; 15(3):306-12. DOI: 10.1038/nm.1931
Source: PubMed


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.

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Available from: Irene Patzak, Oct 11, 2015
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    • "LAD type 1 and 2 mutations are rare and result in defects in leukocyte recruitment and severe recurrent infections in these patients (for a review, see van de Vijver et al. 2012). Leukocytes from patients that have mutations in kindlin-3 (FERMT3 gene), a cytosolic protein that binds to the cytoplasmic domains of β1, β2 and β3 integrins, fail to activate these three integrins and, as a result, emigrate poorly into tissues (Svensson et al. 2009). This disorder is called LAD type III. "
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    ABSTRACT: This issue of Tissue Barriers contains the inaugural special issue devoted to recent advances in barrier function of endothelial and epithelial cells. We used this opportunity to invite experts in vascular endothelial cell biology and epithelial cell biology to comment on critical questions and problems in permeability of organ and tissue barriers, and to provide insight into common areas in these fields, namely how these cells maintain homeostasis and response to injury and infection. To complement these reviews, this issue also contains four research articles that explore specific questions related respiratory and intestinal epithelial cell function.
    02/2015; 3(1-2):e1015825. DOI:10.1080/21688370.2015.1015825
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    • "In contrast to C. elegans, which has one kindlin (UNC-112), humans have three kindlins, each encoded by a separate gene (Meves et al., 2009). Inherited mutations in kindlin-1 result in a serious skin disease (Kindler syndrome) (Siegel et al., 2003), and mutations in kindlin-3 result in severe dysfunction of both platelets and leukocytes (leukocyte adhesion deficiency type III) (Moser et al., 2009; Svensson et al., 2009). Kindlin-2 is expressed in the heart and localized to intercalated disks and costameres. "
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    ABSTRACT: We describe a strategy for exploring the function of protein-protein interactions in striated muscle in vivo. We describe our experience using this strategy to study the interaction of UNC-112 (kindlin) with PAT-4 (integrin linked kinase). Random mutagenesis is used to generate a collection of mutants that are screened for lack of binding or gain of binding using a yeast 2-hybrid assay. The mutant proteins are then expressed in transgenic C. elegans to determine their ability to localize in the sarcomere. We emphasize two advantages of this strategy: (1) for studying the interaction of protein A with protein B, when protein A can interact with multiple proteins, and (2) it explores the function of an interaction rather than the absence of, or reduced level of, a protein as can be obtained with null mutants or knockdown by RNAi. We propose that this method can be generalized for studying the meaning of a protein-protein interaction in muscle for any system in which transgenic animals can be generated and their muscles can be imaged.
    Frontiers in Physiology 04/2014; 5:162. DOI:10.3389/fphys.2014.00162 · 3.53 Impact Factor
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    • "Recently, it was discovered that kindlin-3 is mutated in the rare genetic disorder, leukocyte adhesion deficiency type III (LAD-III). Like LAD-I patients, LAD-III patients suffer from recurrent infections, but in addition, the patients have a bleeding phenotype due to deficient platelet integrin activation [14] [15] [16]. In addition, the patients may suffer from osteopetrosis [15], due to deficient integrin-mediated osteoclast bone resorption [17]. "
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    ABSTRACT: Kindlin-3 is a member of the kindlin family of focal adhesion proteins which bind to integrin beta-chain cytoplasmic domains to regulate integrin function. In contrast to kindlin-1 and kindlin-2 proteins, kindlin-3 is expressed mainly in the hematopoietic system. Mutations in kindlin-3 result in the rare genetic disorder, leukocyte adhesion deficiency type III (LAD-III), which is characterized by bleeding and recurrent infections due to deficient beta1, beta2 and beta3 integrin activation in platelets and leukocytes. Here, we review the role of kindlin-3 in integrin activation and in different immune cell functions.
    03/2014; 3(1):37-42.
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