Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity

Gabriela Lopez-Herrera, Giacomo Tampella, Qiang Pan-Hammarström, Peer Herholz, Claudia M Trujillo-Vargas, Kanchan Phadwal, Anna Katharina Simon, Michel Moutschen, Amos Etzioni, Adi Mory, Izhak Srugo, Doron Melamed, Kjell Hultenby, Chonghai Liu, Manuela Baronio, Massimiliano Vitali, Pierre Philippet, Vinciane Dideberg, Asghar Aghamohammadi, Nima RezaeiVictoria Enright, Likun Du, Ulrich Salzer, Hermann Eibel, Dietmar Pfeifer, Hendrik Veelken, Hans Stauss, Vassilios Lougaris, Alessandro Plebani, E Michael Gertz, Alejandro A Schäffer, Lennart Hammarström, Bodo Grimbacher

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)986-1001
Number of pages16
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - 8 Jun 2012


  • Adaptor Proteins, Signal Transducing
  • Agammaglobulinemia
  • Apoptosis
  • Autoimmunity
  • Autophagy
  • B-Lymphocytes
  • Cell Proliferation
  • Child
  • Child, Preschool
  • Chromosome Mapping
  • Female
  • Genetic Linkage
  • Genotype
  • Homozygote
  • Humans
  • Immunologic Deficiency Syndromes
  • Immunophenotyping
  • Male
  • Microscopy, Electron, Transmission
  • Models, Genetic
  • Mutation
  • Pedigree
  • Phenotype


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