Two mutations in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient reveal distinct effects on leukocyte function in vitro

McDowall, Alison; Svensson, Lena; Stanley, Paula; Patzak, Irene; Chakravarty, Probir; Howarth, Kimberley; Sabnis, Himalee; Briones, Michael; Hogg, Nancy

doi:10.1182/blood-2009-08-238709

Cited by 66 publications

(67 citation statements)

References 44 publications

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“…70 However, mutations in FERMT3 (encoding kindlin-3) were later found to account for the phenotype. 46,[71][72][73][74] Kindlin-3 belongs to a family of proteins that cooperate with talin in inside-out integrin activation. 73 Possessing a single FERM (F) domain with 3 subdomains, kindlin-3 binds through its third subdomain (F3) to the membrane distal NXXY motif of the ␤-integrin cytoplasmic tail; this differs from talin, which binds to the membrane proximal NXXY motif.…”

Section: Lad-3 Syndromementioning

confidence: 99%

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Nurden

Fiore

Pillois

2011

Blood

202

269

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Characterized by mucocutaneous bleeding arising from a lack of platelet aggregation to physiologic stimuli, Glanzmann thrombasthenia (GT) is the archetypeinherited disorder of platelets. Transmitted by autosomal recessive inheritance, platelets in GT have quantitative or qualitative deficiencies of the fibrinogen receptor, ␣IIb␤3, an integrin coded by the ITGA2B and ITGB3 genes. Despite advances in our understanding of the disease, extensive phenotypic variability with respect to severity and intensity of bleeding remains poorly understood. Importantly, genetic defects of ITGB3 also potentially affect other tissues, for ␤3 has a wide tissue distribution when present as ␣v␤3 (the vitronectin receptor). We now look at the repertoire of ITGA2B and ITGB3 gene defects, reexamine the relationship between phenotype and genotype, and review integrin structure in the many variant forms. Evidence for modifications in platelet production is assessed, as is the multifactorial etiology of the clinical expression of the disease. Reports of cardiovascular disease and deep vein thrombosis, cancer, brain disease, bone disorders, and pregnancy defects in GT are discussed in the context of the results obtained for mouse models where nonhemostatic defects of ␤3-deficiency or nonfunction are being increasingly described. (Blood. 2011;118(23):5996-6005) IntroductionGlanzmann thrombasthenia (GT) is the most frequently encountered inherited disorder of platelet function. [1][2][3] Patients have a lifelong hemorrhagic syndrome typically characterized by episodes of spontaneous mucocutaneous bleeding. Platelets fail to aggregate in response to stimuli because they lack or have nonfunctional ␣IIb␤3 integrin (formerly known as GPIIb-IIIa). Resting normal platelets are suspected to have ␣IIb␤3 in a bent conformation; when platelets are stimulated, the integrin straightens in parallel to the exposure of determinants essential for the binding of fibrinogen (Fg) or other soluble adhesive proteins. 3,4 The latter assure aggregation by cross-linking adjacent platelets, a process that cannot occur in GT. Elucidation of this pathway led to the development of integrin-blocking drugs that are strong inhibitors of arterial thrombosis, thereby increasing interest in the clinical manifestations of GT. 3,4 Platelet ␣IIb␤3 also transmits the forces generated by intracellular cytoskeletal proteins during clot contraction and platelet spreading, processes that also fail in patients lacking adequate amounts of functional integrin.Although the GT phenotype is well defined, bleeding severity differs considerably between affected persons, even within the same family or ethnic group. 1,2 In this review, we discuss phenotypic variability, present variant types, and identify possible additional effects associated with ␤3 deletion, for although ␣IIb is largely restricted to the megakaryocyte (MK) lineage, ␤3 is much more widespread in its tissue distribution occurring as ␣v␤3, the vitronectin receptor. 5,6 Data for patients will be compared with those obtained for...

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Section: Lad-3 Syndromementioning

confidence: 99%

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Nurden

Fiore

Pillois

2011

Blood

202

269

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“…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].…”

Section: Lad-iiimentioning

confidence: 99%

Leukocyte Beta2-Integrins; Genes and Disease

Morrison¹

2013

J Genet Syndr Gene Ther

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“…Clinically, loss of kindlin-3 expression accounts for the pathogenesis of leukocyte adhesion deficiency type III that is characterized by bleeding disorders and defective recruitment of leukocytes into sites of infection (28,29). Our finding suggests that leukocytes in these patients might have several functional deficiencies of integrin ␣4␤1, including lack of firm cell adhesion mediated by the resting ␣4␤1, less stable ␣4␤1/ VCAM-1 interactions, and higher rolling velocity besides the deficient activation of this integrin via inside-out signaling (26).…”

Section: Kindlin-3 Regulates Resting ␣4␤1-mediated Firm Cell Adhesionmentioning

confidence: 99%

“…Kindlin-3-deficient platelets showed defective activation of ␣IIb␤3 and ␣2␤1 integrins in response to chemokine stimulation (27). In addition, loss of kindlin-3 expression accounts for the rare autosomal human disease named leukocyte adhesion deficiency type III (28,29). Lymphocytes derived from leukocyte adhesion deficiency type III patients showed defective activation of ␣L␤2 and ␣4␤1 integrins upon phorbol 12-myristate 13-acetate stimulation and showed impaired cell spreading and migration (26,30,31).…”

mentioning

confidence: 99%

Kindlin-3 Is Essential for the Resting α4β1 Integrin-mediated Firm Cell Adhesion under Shear Flow Conditions

Lin

Yan

et al. 2016

Journal of Biological Chemistry

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Integrin-mediated rolling and firm cell adhesion are two critical steps in leukocyte trafficking. Integrin ␣4␤1 mediates a mixture of rolling and firm cell adhesion on vascular cell adhesion molecule-1 (VCAM-1) when in its resting state but only supports firm cell adhesion upon activation. The transition from rolling to firm cell adhesion is controlled by integrin activation. Kindlin-3 has been shown to bind to integrin ␤ tails and trigger integrin activation via inside-out signaling. However, the role of kindlin-3 in regulating resting ␣4␤1-mediated cell adhesion is not well characterized. Herein we demonstrate that kindlin-3 was required for the resting ␣4␤1-mediated firm cell adhesion but not rolling adhesion. Knockdown of kindlin-3 significantly decreased the binding of kindlin-3 to ␤1 and downregulated the binding affinity of the resting ␣4␤1 to soluble VCAM-1. Notably, it converted the resting ␣4␤1-mediated firm cell adhesion to rolling adhesion on VCAM-1 substrates, increased cell rolling velocity, and impaired the stability of cell adhesion. By contrast, firm cell adhesion mediated by Mn 2؉ -activated ␣4␤1 was barely affected by knockdown of kindlin-3. Structurally, lack of kindlin-3 led to a more bent conformation of the resting ␣4␤1. Thus, kindlin-3 plays an important role in maintaining a proper conformation of the resting ␣4␤1 to mediate both rolling and firm cell adhesion. Defective kindlin-3 binding to the resting ␣4␤1 leads to a transition from firm to rolling cell adhesion on VCAM-1, implying its potential role in regulating the transition between integrin-mediated rolling and firm cell adhesion.

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Two mutations in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient reveal distinct effects on leukocyte function in vitro

Cited by 66 publications

References 44 publications

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Leukocyte Beta2-Integrins; Genes and Disease

Kindlin-3 Is Essential for the Resting α4β1 Integrin-mediated Firm Cell Adhesion under Shear Flow Conditions

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