{"id":39522,"date":"2025-08-01T12:00:00","date_gmt":"2025-08-01T10:00:00","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2025\/08\/01\/loss-of-malt1-function-in-a-patient-with-combined-immunodeficiency-a-novel-pathogenic-variant-and-immunological-insights\/"},"modified":"2025-08-01T12:00:00","modified_gmt":"2025-08-01T10:00:00","slug":"loss-of-malt1-function-in-a-patient-with-combined-immunodeficiency-a-novel-pathogenic-variant-and-immunological-insights","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2025\/08\/01\/loss-of-malt1-function-in-a-patient-with-combined-immunodeficiency-a-novel-pathogenic-variant-and-immunological-insights\/","title":{"rendered":"Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights"},"content":{"rendered":"
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J Clin Immunol<\/b>. 2025 Aug 1;45(1):119. doi: 10.1007\/s10875-025-01921-y.<\/p>\n

ABSTRACT<\/b><\/p>\n

BACKGROUND AND OBJECTIVES: 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.<\/p>\n

METHODS: 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.<\/p>\n

RESULTS: 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-\u03baB activation was confirmed by reduced phosphorylation of the p65 subunit, resulting in deficient production of IL-2 and TNF-\u03b1. 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.<\/p>\n

CONCLUSIONS: 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.<\/p>\n

PMID:40748513<\/a> | DOI:10.1007\/s10875-025-01921-y<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"

J Clin Immunol. 2025 Aug 1;45(1):119. doi: 10.1007\/s10875-025-01921-y. ABSTRACT BACKGROUND AND OBJECTIVES: 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 … Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[69,42],"tags":[],"class_list":["post-39522","post","type-post","status-publish","format-standard","hentry","category-journal-of-clinical-immunology","category-publicaciones"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/39522","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=39522"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/39522\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=39522"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=39522"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=39522"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}