title: Leukocyte adhesion deficiency-I variant syndrome (LAD-Iv, LAD-III): molecular characterization of the defect in an index family.
abstract: Leukocyte adhesion deficiencies are rare clinical syndromes of impaired host defense that provide novel insights into regulation of immune and inflammatory responses. Leukocyte adhesion deficiency (LAD)-I variant (LAD-Iv), also called LAD-III, is a unique disorder in which inside-out signaling of β₁, β₂, and β₃ integrins on leukocytes and platelets is disrupted, leading to impaired cellular adhesion, recurrent infections, and bleeding. We originally reported the second patient with this disorder to be identified and characterized the adhesive deficiencies and functional phenotype of this subject's leukocytes. Here, we show that the molecular defect in this index subject is a new mutation in FERMT3 (KINDLIN-3) which encodes KINDLIN-3, a cytoskeletal protein that interacts with the cytoplasmic tails of β₁, β₂, and β₃ integrins and is required for inside-out and outside-in signaling of these heterodimers. We also report clinical features and previously unrecognized defects in cells from a new patient, a sibling of the original subject that we described who carries the same FERMT3 mutation. Mutations in FERMT3 have now been shown to be the basis for LAD-Iv/LAD-III in each of the four original patients or families that established this syndrome, including the family that we describe.
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA. estelle.harris@u2m2.utah.edu
authors.forename: Estelle S
authors.initials: ES
authors.lastname: Harris
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Smith
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Springett
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Weyrich
authors.forename: Guy A
authors.initials: GA
authors.lastname: Zimmerman
mesh_terms: D016026:Bone Marrow Transplantation; D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D002461:Cell Line, Transformed / Q000473:pathology; D002478:Cells, Cultured / Q000473:pathology; D003241:Consanguinity; D020022:Genetic Predisposition to Disease; D006474:Hemorrhagic Disorders / Q000235:genetics; D006529:Hepatomegaly / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007239:Infections / Q000209:etiology; D019012:Integrin beta1 / Q000378:metabolism; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D007962:Leukocytes / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D020125:Mutation, Missense; D009363:Neoplasm Proteins; D017354:Point Mutation; D012008:Recurrence; D013163:Splenomegaly / Q000235:genetics
chemical_list: D018821:CD18 Antigens; C477322:FERMT3 protein, human; D019012:Integrin beta1; D008565:Membrane Proteins; D009363:Neoplasm Proteins