A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency

被引:106
作者
Jabara, Haifa H. [1 ,2 ]
Ohsumi, Toshiro [3 ,4 ]
Chou, Janet [1 ,2 ]
Massaad, Michel J. [1 ,2 ]
Benson, Halli [1 ]
Megarbane, Andre [5 ]
Chouery, Eliane [5 ]
Mikhael, Raymond [6 ]
Gorka, Oliver [7 ]
Gewies, Andreas [7 ,8 ,9 ]
Portales, Pierre [10 ]
Nakayama, Toshinori [11 ]
Hosokawa, Hiroyuki [11 ]
Revy, Patrick [12 ,13 ]
Herrod, Henry [14 ]
Le Deist, Francoise [15 ]
Lefranc, Gerard [5 ,16 ,17 ]
Ruland, Juergen [7 ,8 ,9 ,18 ]
Geha, Raif S. [1 ,2 ]
机构
[1] Childrens Hosp, Div Immunol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA
[3] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA
[4] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA
[5] St Joseph Univ, Fac Med, Med Genet Unit, Beirut, Lebanon
[6] St Joseph Univ, Hotel Dieu Hosp, Dept Pediat, Beirut, Lebanon
[7] Tech Univ Munich, Klinikum Rechts Isar, Inst Klin Chem & Pathobiochem, D-80290 Munich, Germany
[8] German Canc Consortium DKTK, Heidelberg, Germany
[9] German Canc Res Ctr, Heidelberg, Germany
[10] Ctr Hosp Univ Montpellier, Immunol Lab, Montpellier, France
[11] Chiba Univ, Grad Sch Med, Dept Immunol, Chiba, Japan
[12] Univ Paris 05, Inst Imagine, Univ Sorbonne Paris Cite, Paris, France
[13] INSERM, U768, Paris, France
[14] Lebonheur Childrens Hosp & Med Ctr, Memphis, TN USA
[15] Univ Montreal, Dept Microbiol & Immunol, Montreal, PQ H3C 3J7, Canada
[16] Inst Human Genet, CNRS UPR 1142, Montpellier, France
[17] Univ Montpellier, F-34059 Montpellier, France
[18] German Ctr Infect Res DZIF, Braunschweig, Germany
基金
美国国家卫生研究院;
关键词
MALT1; combined immunodeficiency (CID); NF-kappa B; T-CELL; DEFICIENCY; CARD11;
D O I
10.1016/j.jaci.2013.04.047
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
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 I kappa B alpha 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-kappa B 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.
引用
收藏
页码:151 / 158
页数:8
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