title: A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency.
abstract: BACKGROUND
  Combined immunodeficiency (CID) is characterized by severe recurrent infections with normal numbers of T and B lymphocytes but with deficient cellular and humoral immunity. Most cases are sporadic, but autosomal recessive inheritance has been described. In most cases, the cause of CID remains unknown.
  
  
  OBJECTIVE
  We wanted to identify the genetic cause of CID in 2 siblings, the products of a first-cousin marriage, who experienced recurrent bacterial and candidal infections with bronchiectasis, growth delay, and early death.
  
  
  METHODS
  We performed immunologic, genetic, and biochemical studies in the 2 siblings, their family members, and healthy controls. Reconstitution studies were performed with T cells from mucosa-associated lymphoid tissue lymphoma-translocation gene 1-deficient (Malt1(-/-)) mice.
  
  
  RESULTS
  The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients. Whole genome sequencing of 1 patient and her parents, followed by DNA sequencing of family members and healthy controls, showed the presence in both patients of a homozygous missense mutation in MALT1 that resulted in loss of protein expression. Analysis of T cells that were available on one of the patients showed severely impaired IκBα degradation and IL-2 production after activation, 2 events that depend on MALT1. In contrast to wild-type human MALT1, the patients' MALT1 mutant failed to correct defective nuclear factor-κB activation and IL-2 production in MALT1-deficient mouse T cells.
  
  
  CONCLUSIONS
  An autosomal recessive form of CID is associated with homozygous mutations in MALT1. If future patients are found to be similarly affected, they should be considered as candidates for allogeneic hematopoietic cell transplantation.
authors.affiliation: Division of Immunology, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Haifa H
authors.initials: HH
authors.lastname: Jabara
authors.forename: Toshiro
authors.initials: T
authors.lastname: Ohsumi
authors.forename: Janet
authors.initials: J
authors.lastname: Chou
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Massaad
authors.forename: Halli
authors.initials: H
authors.lastname: Benson
authors.forename: Andre
authors.initials: A
authors.lastname: Megarbane
authors.forename: Eliane
authors.initials: E
authors.lastname: Chouery
authors.forename: Raymond
authors.initials: R
authors.lastname: Mikhael
authors.forename: Oliver
authors.initials: O
authors.lastname: Gorka
authors.forename: Andreas
authors.initials: A
authors.lastname: Gewies
authors.forename: Pierre
authors.initials: P
authors.lastname: Portales
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hosokawa
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
authors.forename: Henry
authors.initials: H
authors.lastname: Herrod
authors.forename: Francoise
authors.initials: F
authors.lastname: Le Deist
authors.forename: Gerard
authors.initials: G
authors.lastname: Lefranc
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020169:Caspases / Q000032:analysis / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D051550:I-kappa B Kinase; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein