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 deficient cellular and humoral immunity. Most cases are sporadic, but autosomal recessive inheritance has been described. In the majority of cases, the cause of CID remains unknown. OBJECTIVE To identify the genetic cause of CID in two siblings, the products of a first-cousin marriage, who suffered from recurrent bacterial and candidal infections with bronchiectasis, growth delay, and early death. METHODS We performed immunologic, genetic, and biochemical studies in the two siblings, their family members and healthy controls. Reconstitution studies were performed using T cells from 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 (WGS) of one patient and her parents, followed by DNA sequencing of family members and healthy controls, revealed 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 revealed severely impaired IκBα degradation and IL-2 production after activation, two events that depend on MALT1. In contrast to wild type human MALT1, the patients' MALT1 mutant failed to correct defective NF-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. Should future patients found to be similarly affected they should be considered as candidates for allogeneic hematopoietic cell transplantation.

Deficiency of MALT1 Paracaspase Activity Results in Unbalanced Regulatory and Effector T and B Cell Responses Leading to Multiorgan Inflammation

“…More importantly, what is the relevance of MALT1 protease activity in humans? Polymorphisms in the Malt1 gene have been associated with combined immunodeficiency (45)(46)(47). However, in all cases the mutations resulted in a complete deficiency of the protein or very low MALT1 levels because of protein instability.…”

Mendelian Genetics of Human Susceptibility to Fungal Infection

“…Remarkably, although Card9 is indispensable for control of IA, tuberculosis, and listeriosis in mice Dorhoi et al 2010;Jhingran et al 2012), no infections by molds, intracellular bacteria or mycobacteria have thus far been reported in CARD9-deficient humans. Of note, MALT1 mutations were reported recently to result in an autosomal recessive SCID phenotype with severe bacterial infections and associated mucosal candidiasis of the gastrointestinal tract but no systemic fungal disease (Jabara et al 2013). Identification of more patients with MALT1 mutations and of patients with BCL-10 mutations will be required to draw firm conclusions with regard to the differential role of CARD9, BCL-10, and MALT1 in mediating mucosal and systemic antifungal immune responses.…”

Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity

“…Unfortunately, it is not always easy to distinguish between these conditions, and it can therefore be difficult to assess prognosis. Inborn defects of the CBM complex -consisting of caspase recruitment domain-containing (CARD) family adaptors, B cell CLL/lymphoma 10 (BCL10), and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) -have recently been shown to underlie SCID, CID, and other immunological phenotypes (6)(7)(8)(9)(10). The CBM complex is involved in NF-κB activation after stimulation of various receptors on lymphoid, myeloid, and epithelial cells (11)(12)(13).…”