A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans

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Abstract
In this issue, three reports show that Kindlin-3 is crucial for activation of multiple classes of integrins in several types of hematopoietic cells. In mice, Kindlin-3 was previously shown to be important for platelet activation and blood clotting, and Moser et al. now show its importance in leukocytes for adhesion to the endothelium. In humans, Svensson et al. and Malinin et al. show that mutation of the gene encoding Kindlin-3 is associated with a disease syndrome involving severe bleeding, infection and osteopetrosis, which Malinin et al. showed could be corrected by bone marrow transplantation ( pages 249–250 , 300–305 and 306–312 ). Monogenic deficiency diseases provide unique opportunities to define the contributions of individual molecules to human physiology and to identify pathologies arising from their dysfunction. Here we describe a deficiency disease in two human siblings that presented with severe bleeding, frequent infections and osteopetrosis at an early age. These symptoms are consistent with but more severe than those reported for people with leukocyte adhesion deficiency III (LAD-III). Mechanistically, these symptoms arose from an inability to activate the integrins expressed on hematopoietic cells, including platelets and leukocytes. Immortalized lymphocyte cell lines isolated from the two individuals showed integrin activation defects. Several proteins previously implicated in integrin activation, including Ras-associated protein-1 (RAP1)1 and calcium and diacylglycerol-regulated guanine nucleotide exchange factor-1 (CALDAG-GEF1)2, were present and functional in these cell lines. The genetic basis for this disease was traced to a point mutation in the coding region of the KINDLIN3 (official gene symbol FERMT3) gene3. When wild-type KINDLIN-3 was expressed in the immortalized lymphocytes, their integrins became responsive to activation signals. These results identify a genetic disease that severely compromises the health of the affected individuals and establish an essential role of KINDLIN-3 in integrin activation in humans. Furthermore, allogeneic bone marrow transplantation was shown to alleviate the symptoms of the disease.