title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
abstract: Human T-cell function is dependent on T-cell antigen receptor (TCR) and co-signalling as evidenced by immunodeficiencies affecting TCR-dependent signalling pathways. Here, we show four human patients with EBV+disseminated smooth muscle tumours that carry two homozygous loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and myosin 1 linker 2. These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function, as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders. Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics.
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Lindwurmstrasse 4, D-80337 Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Schober
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Lindwurmstrasse 4, D-80337 Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Magg
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Ismaninger Strasse 22, D-81675 Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Laschinger
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Lindwurmstrasse 4, D-80337 Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rohlfs
authors.affiliation: Laboratory of Clinical Genomics, Federal University of Minas Gerais, 190 Professor Alfredo Balena Avenida, Belo Horizonte 30130-100, Brazil.
authors.forename: N D
authors.initials: ND
authors.lastname: Linhares
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Lindwurmstrasse 4, D-80337 Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Puchalka
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Ismaninger Strasse 22, D-81675 Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Weisser
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Ismaninger Strasse 22, D-81675 Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Fehlner
authors.affiliation: Research Unit Gene Vectors, Helmholtz Zentrum München (HMGU)-German Research Center for Environmental Health, Marchioninistrasse 25, D-81377 Munich, Germany.|Children's Hospital, Technische Universität München (TUM), Munich D-80804, Germany.|German Centre for Infection Research (DZIF), Trogerstrasse 30, D-81675 Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Mautner
authors.affiliation: Institute of Pathology, Ludwig-Maximilians-Universität (LMU), Thalkirchner Strasse 36, D-80337 Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Walz
authors.affiliation: Institute of Pathology, Hannover Medical School (MHH), Carl-Neuberg-Strasse 1, D-30625 Hanover, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Hussein
authors.affiliation: Department of Diagnostic Virology, Max von Pettenkofer-Institute, Ludwig-Maximilians-Universität (LMU), Pettenkoferstrasse 9a, D-80336 Munich, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Jaeger
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Lindwurmstrasse 4, D-80337 Munich, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Kammer
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Lindwurmstrasse 4, D-80337 Munich, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Schmid
authors.affiliation: Department of Pediatric Gastroenterology, Federal University of Minas Gerais, 110 Prof. Alfredo Balena Avenida, Belo Horizonte 30130-100, Brazil.
authors.forename: M
authors.initials: M
authors.lastname: Bahia
authors.affiliation: Laboratory of Clinical Genomics, Federal University of Minas Gerais, 190 Professor Alfredo Balena Avenida, Belo Horizonte 30130-100, Brazil.
authors.forename: S D
authors.initials: SD
authors.lastname: Pena
authors.affiliation: Research Unit Gene Vectors, Helmholtz Zentrum München (HMGU)-German Research Center for Environmental Health, Marchioninistrasse 25, D-81377 Munich, Germany.|Children's Hospital, Technische Universität München (TUM), Munich D-80804, Germany.|German Centre for Infection Research (DZIF), Trogerstrasse 30, D-81675 Munich, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Behrends
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Lindwurmstrasse 4, D-80337 Munich, Germany.
authors.forename: B H
authors.initials: BH
authors.lastname: Belohradsky
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Lindwurmstrasse 4, D-80337 Munich, Germany.|German Centre for Infection Research (DZIF), Trogerstrasse 30, D-81675 Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Klein
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Lindwurmstrasse 4, D-80337 Munich, Germany.|German Centre for Infection Research (DZIF), Trogerstrasse 30, D-81675 Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Hauck
mesh_terms: D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D015398:Signal Transduction
chemical_list: C547525:CARMIL1 protein, human; D018106:CD28 Antigens; D008840:Microfilament Proteins