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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
immunology and microbiology
A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency
Journal of Allergy and Clinical Immunology, Volume 132, No. 1, Year 2013
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Description
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 lymphomatranslocation 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 IkBa 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. © 2013 American Academy of Allergy, Asthma &Immunology.
Authors & Co-Authors
Jabara, Haifa H.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
Ohsumi, Toshiro K.
United States, Boston
Massachusetts General Hospital
United States, Boston
Harvard Medical School
Chou, Janet S.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
Massaad, Michel J.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
Benson, Halli
United States, Boston
Boston Children's Hospital
Megarbane, Andre
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Chouery, Éliane
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Mikhael, Raymond
Lebanon, Beirut
Hôtel-dieu de France Hospital
Gorka, Oliver
Germany, Munich
Klinikum Rechts Der Isar
Gewies, Andreas
Germany, Munich
Klinikum Rechts Der Isar
Germany, Heidelberg
German Cancer Research Center
Portales, Pierre
France, Montpellier
Centre Hospitalier Universitaire de Montpellier
Nakayama, Toshinori
Japan, Chiba
Chiba University
Hosokawa, Hiroyuki
Japan, Chiba
Chiba University
Revy, Patrick
France, Paris
Sorbonne Paris Cité Université Paris Diderot
Herrod, Henry G.
United States, Memphis
Le Bonheur Children's Hospital
Deist, Francoise Le
Canada, Montreal
University of Montreal
Lefranc, Gérard
Lebanon, Beirut
Université Saint-joseph de Beyrouth
France, Montpellier
Université de Montpellier
Ruland, Jürgen
Germany, Munich
Klinikum Rechts Der Isar
Germany, Heidelberg
German Cancer Research Center
Germany, Braunschweig
Helmholtz Centre for Infection Research Hzi
Geha, Raif S.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
Statistics
Citations: 19
Authors: 19
Affiliations: 14
Identifiers
Doi:
10.1016/j.jaci.2013.04.047
ISSN:
00916749
e-ISSN:
10976825
Research Areas
Cancer
Genetics And Genomics
Health System And Policy