title: A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans.
abstract: 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) and calcium and diacylglycerol-regulated guanine nucleotide exchange factor-1 (CALDAG-GEF1), 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) gene. 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.
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, NB50, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Nikolay L
authors.initials: NL
authors.lastname: Malinin
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Jeongsuk
authors.initials: J
authors.lastname: Choi
authors.forename: Alieta
authors.initials: A
authors.lastname: Ciocea
authors.forename: Olga
authors.initials: O
authors.lastname: Razorenova
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Ma
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Podrez
authors.forename: Michael
authors.initials: M
authors.lastname: Tosi
authors.forename: Donald P
authors.initials: DP
authors.lastname: Lennon
authors.forename: Arnold I
authors.initials: AI
authors.lastname: Caplan
authors.forename: Susan B
authors.initials: SB
authors.lastname: Shurin
authors.forename: Edward F
authors.initials: EF
authors.lastname: Plow
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Byzova
mesh_terms: D016026:Bone Marrow Transplantation; D002461:Cell Line, Transformed; D006801:Humans; D016023:Integrins / Q000502:physiology*; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics / Q000601:surgery; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D017354:Point Mutation
chemical_list: C477322:FERMT3 protein, human; D016023:Integrins; D008565:Membrane Proteins; D009363:Neoplasm Proteins