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.
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.
Laboratory of Immunogenetics of Diseases, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain; Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain. Electronic address: rebeca.perez@idipaz.es.
Rebeca
R
Pérez de Diego
Clinical Immunology Department, San Carlos Clinical Hospital, Madrid, Spain.
Silvia
S
Sánchez-Ramón
Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain; Laboratory of Tumor Immunology, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain.
Eduardo
E
López-Collazo
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY.
Rubén
R
Martínez-Barricarte
Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain; Laboratory of Tumor Immunology, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain.
Carolina
C
Cubillos-Zapata
Immunology Unit, La Paz University Hospital, Madrid, Spain.
Antonio
A
Ferreira Cerdán
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Howard Hughes Medical Institute, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; University Paris Descartes, Imagine Institute, Paris, France; Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France.
Jean-Laurent
JL
Casanova
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; University Paris Descartes, Imagine Institute, Paris, France.
Anne
A
Puel
D056704:Adaptive Immunity; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000378:metabolism; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006162:Guanylate Cyclase / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009154:Mutation / Q000235:genetics; D009181:Mycoses / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; C430880:CARD10 protein, human; C505855:CARD9 protein, human; D009363:Neoplasm Proteins; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426242:CARD11 protein, human; D006162:Guanylate Cyclase
B-cell lymphoma 10; CARMA1; Primary immunodeficiency; caspase recruitment domain 9; combined immunodeficiency; mucosa-associated lymphoid tissue lymphoma-translocation gene 1