Genetic errors of the human caspase recruitment domain–B-cell lymphoma 10–mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity

• Published in: Journal of allergy and clinical immunology 2015-11, Vol.136 (5), p.1139-1149
• Main Authors: Pérez de Diego, Rebeca, PhD, Sánchez-Ramón, Silvia, MD, PhD, López-Collazo, Eduardo, PhD, Martínez-Barricarte, Rubén, PhD, Cubillos-Zapata, Carolina, PhD, Ferreira Cerdán, Antonio, MD, PhD, Casanova, Jean-Laurent, MD, PhD, Puel, Anne, PhD
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Age; Allergy and Immunology; Amino acids; Animals; B-Cell CLL-Lymphoma 10 Protein; B-cell lymphoma 10; Biopsy; CARD Signaling Adaptor Proteins - genetics; CARD Signaling Adaptor Proteins - metabolism; CARMA1; caspase recruitment domain 9; Caspases - genetics; Caspases - metabolism; combined immunodeficiency; Cytomegalovirus; Genetic Predisposition to Disease; Guanylate Cyclase - genetics; Humans; Immunity, Innate; Immunoglobulins; Immunologic Deficiency Syndromes - genetics; Inflammatory bowel disease; Kinases; Lymphocytes; Mice; Mice, Knockout; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; mucosa-associated lymphoid tissue lymphoma-translocation gene 1; Mutation; Mutation - genetics; Mycoses - genetics; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Patients; Polymorphism, Genetic; Primary immunodeficiency; Proteins; Streptococcus infections; Tetanus
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2015.06.031

Three members of the caspase recruitment domain (CARD) family of adaptors (CARD9, CARD10, and CARD11) are known to form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). These 3 CARD-BCL10-MALT1 (CBM) complexes activate nuclear factor κB in both the innate and adaptive arms of immunity. Human inherited defects of the 3 components of the CBM complex, including the 2 adaptors CARD9 and CARD11 and the 2 core components BCL10 and MALT1, have recently been reported. Biallelic loss-of-function mutant alleles underlie several different immunologic and clinical phenotypes, which can be assigned to 2 distinct categories. Isolated invasive fungal infections of unclear cellular basis are associated with CARD9 deficiency, whereas a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1, and BCL10 deficiencies. Interestingly, human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice. Moreover, germline and somatic gain-of-function mutations of MALT1 , BCL10 , and CARD11 have also been found in patients with other lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including loss-of-function and gain-of-function mutations, highlights the contribution of each of the components of the CBM complex to human immunity.