Novel aspects of Kindlin‐3 function in humans based on a new case of leukocyte adhesion deficiency III

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 β1 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 β1 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.