title: Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT.
abstract: The adapter protein linker for activation of T cells (LAT) is a critical signaling hub connecting T cell antigen receptor triggering to downstream T cell responses. In this study, we describe the first kindred with defective LAT signaling caused by a homozygous mutation in exon 5, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signal propagation. The three patients presented from early childhood with combined immunodeficiency and severe autoimmune disease. Unlike in the mouse counterpart, reduced numbers of T cells were present in the patients. Despite the reported nonredundant role of LAT in Ca(2+) mobilization, residual T cells were able to induce Ca(2+) influx and nuclear factor (NF) κB signaling, whereas extracellular signal-regulated kinase (ERK) signaling was completely abolished. This is the first report of a LAT-related disease in humans, manifesting by a progressive combined immune deficiency with severe autoimmune disease.
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Baerbel
authors.initials: B
authors.lastname: Keller
authors.affiliation: Department of Pediatric Hematology Oncology, Ruth Rappaport Children's Hospital, Rambam Health Care Campus, Haifa 3109601, Israel.
authors.forename: Irina
authors.initials: I
authors.lastname: Zaidman
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, 79106 Freiburg, Germany Department of Molecular Immunology, Faculty of Biology, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, 79104 Freiburg, Germany.
authors.forename: O Sascha
authors.initials: OS
authors.lastname: Yousefi
authors.affiliation: Department of Pathology, Rambam Health Care Campus, Haifa 3109601, Israel.
authors.forename: Dov
authors.initials: D
authors.lastname: Hershkovitz
authors.affiliation: Department of Pediatric Hematology Oncology and Bone Marrow Transplantation Unit, Schneider Children's Medical Center of Israel, Petah-Tikva 49202, Israel.
authors.forename: Jerry
authors.initials: J
authors.lastname: Stein
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Unger
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Schachtrup
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 581 85 Linköping, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
authors.affiliation: Blood Coagulation Service and Pediatric Hematology Clinic, Galilee Medical Center, Nahariya 22100, Israel Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 5290002, Israel.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Kuperman
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah Medical Center, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, 79106 Freiburg, Germany Department of Molecular Immunology, Faculty of Biology, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Wolfgang W
authors.initials: WW
authors.lastname: Schamel
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah Medical Center, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, 79106 Freiburg, Germany klaus.warnatz@uniklinik-freiburg.de polina@hadassah.org.il.
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah Medical Center, Hebrew University, Jerusalem 91120, Israel Department of Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Medical Center, Hebrew University, Jerusalem 91120, Israel klaus.warnatz@uniklinik-freiburg.de polina@hadassah.org.il.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D005091:Exons / Q000276:immunology; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C110810:LAT protein, human; D008565:Membrane Proteins; D016328:NF-kappa B