Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency

Abstract

Key Points Functional reversion of a germline CARD11 mutation in T cells is associated with the development of Omenn syndrome. Defective thymic T-cell development and peripheral lymphopenia are no prerequisite for the development of Omenn syndrome.

Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease

“…As a control, we also tested a variant (p.C150L) identified as a somatic reversion mutant that restored NF-kB signaling in T cells from a CARD11-deficient patient with Omenn syndrome. 27 Upon CD3/CD28 stimulation of transfected JPM50.6 cells, 14 of 26 mutants demonstrated significantly reduced NF-kB activation, indicating LOF (Fig 1, A). Two variants (p.P495S and p.R848C) displayed enhanced NF-kB activation only after stimulation; unlike BENTA-associated mutations, these variants did not induce constitutive NF-kB activity.…”

The CBM-opathies—A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex

“…The importance of the CBM complex in adaptive immunity was experimentally established by the fact that B and T cells from mice deficient in Card11, Bcl10 , or Malt1 all displayed impaired cellular activation and proliferation, aberrant cytokine secretion, and blocks in cell differentiation, resulting in diminished serum immunoglobulin levels. These experimental observations were then validated in the intact human system by the recent discovery of individuals suffering from profound immune defects [i.e., combined immunodeficiency (CID) and severe combined immunodeficiency (SCID)] involving germline loss-of-function (LOF) mutations in CARD11 ( 17 – 19 ), BCL10 ( 20 ), and MALT1 ( 21 – 23 , 24 ) (Figure 1 ). While human deficiency of each of the CBM components has some unique defining clinical features (e.g., gastrointestinal inflammation seen in MALT1 deficiency or susceptibility to Pneumocystis jirovecii pneumonia (PJP) typical for CARD11 deficiency), as testament to their highly synergistic activities, many phenotypic manifestations are shared across these CBM deficiencies.…”

“…Germline homozygous loss-of-function (LOF) mutations in CARD11 are associated with SCID (OMIM 615206) ( 17 – 19 ) (Table 2 ). To date, there have been three reported cases of complete CARD11 deficiency and they were discovered by whole exome sequencing (WES) or directed Sanger sequencing, with mutations localizing to either the CC ( 19 ) or GUK ( 17 , 18 ) domains.…”

“…Recent discoveries have now moved beyond relatively simple LOF mutations, and there is now an interesting spectrum of additional clinical phenotypes attributed to CARD11 mutations ( 25 ), with gain-of-function mutations causing “ B cell E xpansion with N F-κB and T cell A nergy” (BENTA) disease ( 26 – 30 ), hypomorphic dominant-interfering mutations causing combined immunodeficiency with atopic disease “ C ARD11-associated A topy with D ominant I nterference of N F-κB S ignaling” (CADINS) ( 31 , 32 ), and loss-of-function mutations with somatic reversion associated with Omenn syndrome ( 19 ) (Figure 1 ).…”

30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology

“…However, the expansion of a single T-cell clone perturbed immune homeostasis and led to massive T cell infiltration into the skin causing progressive eczema and erythroderma, accompanied by lymphadenopathy and hepatosplenomegaly. Furthermore, the oligoclonal T cells did not provide sufficiently broad immune protection against uncontrolled CMV infections and multiple bouts of sepsis caused by Staphylococcus aureus, Enterococcus, and Pseudomonas that eventually proved fatal to the child at 16 months of age (Fuchs et al, 2015). …”