Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological...

Germline pathogenic variants in the mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) encodes a caspase-like protease that plays a crucial role in the caspase recruitment domain (CARD)-B-cell lymphoma 10 (BCL10)-MALT1 (CBM) complex. This complex mediates the activation of nuclear factor-kB (NF-kB) pathway and are associated with diverse human diseases including combine immunodeficiency (CID), lymphoproliferation and others. This study aimed to determine the underlying cause of immune deficiency and immune dysregulation in a patient presented with recurrent respiratory infections, aphthous ulcers, dermatitis, chronic diarrhea, failure to thrive and early death.

Clinical and laboratory records were reviewed. Patients underwent next-generation sequencing (NGS), and analysis of genomic DNA was performed on the patient and her parents. Lymphocyte subsets, MALT1 expression and NF-kB signaling was evaluated by flow cytometry, RT-PCR and immunoblotting.

The patient carried a novel pathogenic biallelic loss-of-function variant in MALT1 (c.1411G > A; p.D471N) located in the caspase-like domain, leading to severely reduced MALT1 protein expression. Impaired CBM-mediated NF-κB activation was confirmed by reduced phosphorylation of the p65 subunit, resulting in deficient production of IL-2 and TNF-α. This functional defect caused lower Tfr and Treg cells, a normal proportion of Tfh cells, with higher expression of activation markers PD-1 and ICOS. The patient displayed low NK cell and B cell counts, together with a developmental block at the transitional B cell stage. Additionally, the proportion of marginal zone-like B cells (MZB-like) was markedly decreased, indicating impaired B cell differentiation.

Human MALT1 deficiency causes profound CID by impairing CBM-mediated NF-kB signaling and MALT1-paracaspase activity. Consistent with the reported variants located in the caspase-like domain, our patient presented with an inflammatory phenotype, supporting the notion that the MALT1 D471N mutation phenocopies a partial loss of both MALT1 scaffolding function and paracaspase activity. Prompt hematopoietic stem cell transplantation (HSCT) is highly recommended as an effective therapy for MALT1 deficiency.