Novel aspects of Kindlin-3 function in humans based on a new case of leukocyte adhesion deficiency III.
J Thromb Haemost
; 10(7): 1397-408, 2012 Jul.
Article
de En
| MEDLINE
| ID: mdl-22564402
ABSTRACT
BACKGROUND:
Kindlin-3 is a novel integrin activator in hematopoietic cells, and its deficiency leads to immune problems and severe bleeding, known as leukocyte adhesion deficiency III (LAD-III). Our current understanding of Kindlin-3 function primarily relies on analysis of animal models or cell lines.OBJECTIVES:
To understand the functions of Kindlin-3 in human primary blood cells. PATIENTS/METHODS:
We analyzed primary and immortalized hematopoietic cells obtained from a new LAD-III patient with immune problems, bleeding, a history of anemia, and abnormally shaped red blood cells.RESULTS:
The patient's white blood cells (WBCs) and platelets showed defects in agonist-induced integrin activation and botrocetin-induced platelet agglutination. Primary leukocytes from this patient exhibited abnormal activation of ß(1) integrin. Integrin activation defects were responsible for the observed deficiency in the botrocetin-induced platelet response. Analysis of patient genomic DNA revealed a novel mutation in the Kindlin3 gene. The mutation abolished Kindlin-3 expression in primary WBCs and platelets, owing to abnormal splicing. Kindlin-3 is expressed in red blood cells (RBCs), and its deficiency is proposed to lead to abnormally shaped RBCs. Immortalized patient WBCs expressed a truncated form of Kindlin-3 that was not sufficient to support integrin activation. Expression of Kindlin-3 cDNA in immortalized patient WBCs rescued integrin activation defects, whereas overexpression of the truncated form did not.CONCLUSIONS:
Kindlin-3 deficiency impairs integrin function, including activation of ß(1) integrin. Abnormalities in glycoprotein Ib-IX function in Kindlin-3-deficient platelets are secondary to integrin defects. The region of Kindlin-3 encoded by exon 11 is crucial for its ability to activate integrins in humans.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Déficit d'adhérence leucocytaire
/
Protéines membranaires
/
Protéines tumorales
Type d'étude:
Prognostic_studies
Limites:
Child
/
Female
/
Humans
Langue:
En
Journal:
J Thromb Haemost
Sujet du journal:
HEMATOLOGIA
Année:
2012
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique