title: Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity.
abstract: Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
authors.affiliation: Department of Immunology, Division of Infection and Immunity, University College London, Royal Free Hospital, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Lopez-Herrera
authors.forename: Giacomo
authors.initials: G
authors.lastname: Tampella
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pan-Hammarström
authors.forename: Peer
authors.initials: P
authors.lastname: Herholz
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Trujillo-Vargas
authors.forename: Kanchan
authors.initials: K
authors.lastname: Phadwal
authors.forename: Anna Katharina
authors.initials: AK
authors.lastname: Simon
authors.forename: Michel
authors.initials: M
authors.lastname: Moutschen
authors.forename: Amos
authors.initials: A
authors.lastname: Etzioni
authors.forename: Adi
authors.initials: A
authors.lastname: Mory
authors.forename: Izhak
authors.initials: I
authors.lastname: Srugo
authors.forename: Doron
authors.initials: D
authors.lastname: Melamed
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.forename: Chonghai
authors.initials: C
authors.lastname: Liu
authors.forename: Manuela
authors.initials: M
authors.lastname: Baronio
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Vitali
authors.forename: Pierre
authors.initials: P
authors.lastname: Philippet
authors.forename: Vinciane
authors.initials: V
authors.lastname: Dideberg
authors.forename: Asghar
authors.initials: A
authors.lastname: Aghamohammadi
authors.forename: Nima
authors.initials: N
authors.lastname: Rezaei
authors.forename: Victoria
authors.initials: V
authors.lastname: Enright
authors.forename: Likun
authors.initials: L
authors.lastname: Du
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.forename: Hendrik
authors.initials: H
authors.lastname: Veelken
authors.forename: Hans
authors.initials: H
authors.lastname: Stauss
authors.forename: Vassilios
authors.initials: V
authors.lastname: Lougaris
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: E Michael
authors.initials: EM
authors.lastname: Gertz
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000361:Agammaglobulinemia / Q000235:genetics; D017209:Apoptosis; D015551:Autoimmunity / Q000235:genetics*; D001343:Autophagy; D001402:B-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D016130:Immunophenotyping; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008957:Models, Genetic; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C428703:LRBA protein, human