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CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.

ABSTRACT: BACKGROUND:Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. METHODS:To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. RESULTS:Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. CONCLUSION:Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

SUBMITTER: Magg T

PROVIDER: S-EPMC6799948 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.

Magg Thomas T Shcherbina Anna A Arslan Duran D Desai Mukesh M MM Wall Sarah S Mitsialis Vanessa V Conca Raffaele R Unal Ekrem E Karacabey Neslihan N Mukhina Anna A Rodina Yulia Y Taur Prasad D PD Illig David D Marquardt Benjamin B Hollizeck Sebastian S Jeske Tim T Gothe Florian F Schober Tilmann T Rohlfs Meino M Koletzko Sibylle S Lurz Eberhard E Muise Aleixo M AM Snapper Scott B SB Hauck Fabian F Klein Christoph C Kotlarz Daniel D

Inflammatory bowel diseases 20191001 11

<h4>Background</h4>Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes.<h4>Methods</h4>To identify the molecular etiology in 5 patients from 3 unrelated kindr ...[more]

PMID: 31115454

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Project description:Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents.We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very-early-onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs noninflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture.We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and nuclear factor-?B. Computational studies demonstrated a correlation between the TRIM22-NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. TRIM22 is also associated with antiviral and mycobacterial effectors and markers of inflammation, such as fecal calprotectin, C-reactive protein, and Crohn's disease activity index scores.In WES and targeted exome sequence analyses of an infant with severe IBD characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affects the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22-NOD2 network regulates antiviral and antibacterial signaling pathways that contribute to inflammation. Further study of this network could lead to new disease markers and therapeutic targets for patients with very early and adult-onset IBD.

Dataset Information

CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.

Publications

CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.

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