Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency

Abstract

Combined immunodeficiencies are a heterogeneous collection of primary immune disorders that exhibit defects in T cell development or function, along with impaired B cell activity even in light of normal B cell maturation. CARMIL2 (RLTPR) is a protein involved in cytoskeletal organization and cell migration, which also plays a role in CD28 co-signaling of T cells. Mutations in this protein have recently been reported to cause a novel primary immunodeficiency disorder with variable phenotypic presentations. Here, we describe seven patients from three unrelated, consanguineous multiplex families that presented with dermatitis, esophagitis, and recurrent skin and chest infections with evidence of combined immunodeficiency. Through the use of whole exome sequencing and autozygome-guided analysis, we uncovered two mutations not previously reported (p.R50T and p.L846Sfs) in CARMIL2. Real-time PCR analysis revealed that the biallelic frameshift mutation is under negative selection, likely due to nonsense-mediated RNA decay and leading to loss of detectable protein upon immunoblotting. Protein loss was also observed for the missense mutation, and 3D modeling suggested a disturbance in structural stability due to an increase in the electrostatic energy for the affected amino acid and surrounding residues. Immunophenotyping revealed that patient Treg counts were significantly depressed, and that CD4+ T cells were heavily skewed towards the naïve status. CD3/CD28 signaling impairment was evidenced by reduced proliferative response to stimulation. This work broadens the allelic heterogeneity associated with CARMIL2 and highlights a deleterious missense alteration located outside the leucine-rich repeat of the protein, where all other missense mutations have been reported to date.

Hyper‐IgE in the allergy clinic––when is it primary immunodeficiency?

“…Similar observations have been made for mammalian sterile 20‐like one deficiency, a rare form of combined immunodeficiency, where high IgE levels were found only in three of 10 patients described to date . Recessive defects in the cytoskeletal regulator CARMIL2 manifest with dermatitis and combined immunodeficiency, but only two of seven patients had IgE >1000 IU/mL . A novel somatic STAT5b gain of function has been associated with nonclonal eosinophilia, atopic dermatitis, urticaria and diarrhoea in two paediatric patients; however, serum IgE was only elevated in one .…”

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

“…Previous studies found that T cell proliferation was also impaired in patients with CARMIL2 deficiencies [6,8,11]. Based on those results, we evaluated T cell proliferation in our cohort.…”

“…The fundamental value of CARMIL2 for immune defense was also recently proven as patients with bi‐allelic CARMIL2 mutations were diagnosed. Although rare, reports of affected patients have recently been accumulating [1,4,6‐12]. CARMIL2 deficiency is characterized by the reduced regulatory T cell (T reg ) counts and impaired T cell activation, which is attributed to a defect in CD28‐mediated co‐stimulation [4,7‐9].…”

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

“…Similarly, an RLTPR deficiency that caused a selective defect in CD28 co‐stimulation in T cells was recently reported in more than 20 patients, whom none of them has developed EBV‐driven B cell lymphoproliferative disorders. Nevertheless, two patients had EBV viremia, and five developed EBV‐associated smooth muscle tumors . RLTPR‐deficient T‐cells were found to be defective in proliferation and effector functions through TCR‐dependent CD28 co‐stimulation.…”