Combined Immunodeficiency Due to MALT1 Mutations, Treated by Hematopoietic Cell Transplantation

• DOI: 10.1007/s10875-014-0125-1
• Publication Date: 2015-01-27T07:42:06Z
• Authors: Divya Punwani; Haopeng Wang; Alice Y. Chan; Morton J. Cowan; Jacob Mallott; Uma Sunderam; Marianne Mollenauer; Rajgopal Srinivasan; Steven E. Brenner; Arend Mulder; Frans H. J. Claas; Arthur Weiss; Jennifer M. Puck
• Keywords: Male; Messenger; DNA Mutational Analysis; Gene Expression; Regenerative Medicine; CARMA1; Leukocytes; 2.1 Biological and endogenous factors; combined immunodeficiency; Immunology and Allergy; Child; Skin; Original Research; Cell Line, Transformed; Pediatric; B-Lymphocytes; 0303 health sciences; NF-kappa B; Hematopoietic Stem Cell Transplantation; combined immunodeficiency (CID); Neoplasm Proteins; 3. Good health; Caspases; Child, Preschool; Female; Biotechnology; Signal Transduction; Homologous; Adult; Mononuclear; Immunology; 610; BCL10; Cell Line; Immunophenotyping; 03 medical and health sciences; Rare Diseases; Clinical Research; immune dysregulation; Genetics; Humans; Amino Acid Sequence; Preschool; CARD11; Transplantation; Transplantation Chimera; Biomedical and Clinical Sciences; 5.2 Cellular and gene therapies; Base Sequence; Inflammatory and immune system; erythroderma; Infant, Newborn; Infant; bone marrow transplant/hematopoietic cell transplant; Newborn; Transformed; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; Mutation; Leukocytes, Mononuclear; RNA; Severe Combined Immunodeficiency

A male infant developed generalized rash, intestinal inflammation and severe infections including persistent cytomegalovirus. Family history was negative, T cell receptor excision circles were normal, and engraftment of maternal cells was absent. No defects were found in multiple genes associated with severe combined immunodeficiency. A 9/10 HLA matched unrelated hematopoietic cell transplant (HCT) led to mixed chimerism with clinical resolution. We sought an underlying cause for this patient's immune deficiency and dysregulation.Clinical and laboratory features were reviewed. Whole exome sequencing and analysis of genomic DNA from the patient, parents and 2 unaffected siblings was performed, revealing 2 MALT1 variants. With a host-specific HLA-C antibody, we assessed MALT1 expression and function in the patient's post-HCT autologous and donor lymphocytes. Wild type MALT1 cDNA was added to transformed autologous patient B cells to assess functional correction.The patient had compound heterozygous DNA variants affecting exon 10 of MALT1 (isoform a, NM_006785.3), a maternally inherited splice acceptor c.1019-2A > G, and a de novo deletion of c.1059C leading to a frameshift and premature termination. Autologous lymphocytes failed to express MALT1 and lacked NF-κB signaling dependent upon the CARMA1, BCL-10 and MALT1 signalosome. Transduction with wild type MALT1 cDNA corrected the observed defects.Our nonconsanguineous patient with early onset profound combined immunodeficiency and immune dysregulation due to compound heterozygous MALT1 mutations extends the clinical and immunologic phenotype reported in 2 prior families. Clinical cure was achieved with mixed chimerism after nonmyeloablative conditioning and HCT.