CARMIL2 – Severe Combined Immunodeficiency due to CARMIL2 Deficiency

CARMIL2 deficiency follows an autosomal recessive inheritance and is characterized by impaired T, B, and NK cell function leading to recurrent infections, inflammatory skin manifestations, and immunodeficiency. A novel homozygous stopgain variant c.520C>T (p.Arg174Ter) was identified in a patient presenting with recurrent infections, dermatitis, and nephrotic syndrome due to secondary membranous nephropathy, expanding the phenotypic spectrum of CARMIL2-related immunodeficiency (PMID:39649299). Previous reports in unrelated consanguineous families have described biallelic loss-of-function and missense variants in CARMIL2 across seven patients from three families, presenting with dermatitis, esophagitis, and combined immunodeficiency (PMID:29479355), as well as very early onset IBD-like phenotypes in five patients from three kindreds (PMID:31115454) and autoimmune polyendocrine syndrome in multiple cases (PMID:33723309). These studies confirm an allelic series including frameshift, nonsense, and missense variants with full penetrance by early childhood.

Functional studies demonstrate that CARMIL2 loss-of-function disrupts CD28-mediated co-stimulation, leading to defective NF-κB activation, reduced regulatory and memory T cell populations, diminished cytokine production, and impaired proliferation, as shown by protein expression analyses, immunophenotyping, and in vitro assays (PMID:29479355; PMID:32201938; PMID:34287962). Exogenous interleukin-2 rescues T cell activation and proliferation in vitro, suggesting potential therapeutic avenues (PMID:32201938). The concordance of clinical phenotypes with mechanistic data supports a haploinsufficiency model of pathogenicity for CARMIL2 deficiency. Key take-home: genetic testing for CARMIL2 should be considered in patients with autosomal recessive combined immunodeficiency presenting with nephrotic syndrome or membranous nephropathy.

References

• Indian journal of nephrology • 2024 • Secondary Membranous Nephropathy and Immunodeficiency due to a Novel Biallelic Variant in CARMIL2 PMID:39649299
• Frontiers in immunology • 2018 • Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency PMID:29479355
• Inflammatory bowel diseases • 2019 • CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease PMID:31115454
• Scientific reports • 2021 • Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease PMID:33723309
• Clinical and experimental immunology • 2020 • Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation PMID:32201938
• Allergy • 2022 • Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency PMID:34287962

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