Profound immunodeficiency with severe skin disease explained by concomitant novel CARMIL2 and PLEC1 loss-of-function mutations

Maccari, Maria Elena; Speckmann, Carsten; Heeg, Maximilian; Reimer, Antonia; Casetti, Federica; Has, Cristina; Ehl, Stephan; Castro, Carla

doi:10.1016/j.clim.2019.06.004

Cited by 19 publications

(22 citation statements)

References 11 publications

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“…Colitis and various skin manifestations have been described in patients with CARMIL2 deficiencies [8,10]. In the present study, P2 developed multiple seborrheic keratosis over her trunk and proximal limbs at age 15 years.…”

Section: Discussionsupporting

confidence: 53%

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

Shamriz

Simon

Lev

et al. 2020

Clinical &Amp; Experimental Immunology

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Capping protein regulator and myosin 1 linker 2 (CARMIL2) deficiency is characterized by impaired T cell activation, which is attributed to defective CD28-mediated co-signaling. Herein, we aimed to analyze the effect of exogenous interleukin (IL)-2 on in-vitro T cell activation and proliferation in a family with CARMIL2 deficiency. This study included four children (one male and three females; aged 2·5-10 years at presentation). The patients presented with inflammatory bowel disease and recurrent viral infections. Genetic analysis revealed a novel homozygous 25-base pairs deletion in CARMIL2. Immunoblotting demonstrated the absence of CARMIL2 protein in all four patients and confirmed the diagnosis of CARMIL2 deficiency. T cells were activated in-vitro with the addition of IL-2 in different concentrations. CD25 and interferon (IFN)-γ levels were measured after 48 h and 5 days of activation. CD25 surface expression on activated CD8 + and CD4 + T cells was significantly diminished in all patients compared to healthy controls. Additionally, CD8 + T cells from all patients demonstrated signifi-cantly reduced IFN-γ production. When cells derived from CARMIL2deficient patients were treated with IL-2, CD25 and IFN-γ production increased in a dose-dependent manner. T cell proliferation, as measured by Cell Trace Violet, was impaired in one patient and it was also rescued with IL-2. In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients. Thus, IL-2 should be further studied as a potential therapeutic modality for these patients.

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Section: Discussionsupporting

confidence: 53%

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

Shamriz

Simon

Lev

et al. 2020

Clinical &Amp; Experimental Immunology

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“…These data conclusively support the pathogenicity of this novel CARMIL2 variant, p.Gln455_Leu464del, affecting both the numbers and function of T cell and B cell subsets. While we were unable to evaluate the healthy older siblings since they resided in a different country, the genetic, immunologic, and phenotypic data available for the affected siblings and their parents is consistent with an autosomal recessive, completely-penetrant LOF in CARMIL2, similar to previous familial segregation analyses (1)(2)(3)(4)(5)(6)(7)(8)(9). Shared phenotypic findings in the affected brothers include severe growth failure refractory to exogenous growth hormone and IBD therapy (in the case of the proband), and EBV-SMTs.…”

Section: Resultssupporting

confidence: 73%

“…CARMIL2 (RLTPR) is essential for CD28-mediated T cell co-stimulation, and not only promotes actin polymerization at the immunological synapse and leading edge of migrating cells, but can also modulate signaling in B, NK, and some myeloid cells. The clinical phenotype is heterogeneous and includes recurrent infections, eczematous or psoriaform dermatitis, inflammatory bowel disease (IBD), and malignancy (1)(2)(3)(4)(5)(6)(7)(8)(9). We report a novel homozygous CARMIL2 LOF variant presenting with growth failure and Epstein Barr Virus smooth muscle tumors (EBV-SMTs) in two Saudi Arabian brothers born to consanguineous parents.…”

Section: Introductionmentioning

confidence: 99%

A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors

et al. 2020

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CARMIL2 deficiency is a rare combined immunodeficiency (CID) characterized by defective CD28-mediated T cell co-stimulation, altered cytoskeletal dynamics, and susceptibility to Epstein Barr Virus smooth muscle tumors (EBV-SMTs). Case reports associated with EBV-SMTs are limited. We describe herein a novel homozygous CARMIL2 variant (c.1364_1393del) in two Saudi Arabian male siblings born to consanguineous parents who developed EBV-SMTs. CARMIL2 protein expression was significantly reduced in CD4+ T cells and CD8+ T cells. T cell proliferation on stimulation with soluble (s) anti-CD3 or (s) anti-CD3 plus anti-CD28 antibodies was close to absent in the proband, confirming altered CD28-mediated co-signaling. CD28 expression was substantially reduced in the proband's T cells, and was diminished to a lesser degree in the T cells of the younger sibling, who has a milder clinical phenotype. Defects in both T and B cell compartments were observed, including absent central memory CD8+ T cells, and decreased frequencies of total and class-switched memory B cells. FOXP3+ regulatory T cells (Treg) were also quantitatively decreased, and furthermore CD25 expression within the Treg subset was substantially reduced. These data confirm the pathogenicity of this novel loss-of-function (LOF) variant in CARMIL2 and expand the genotypic and phenotypic spectrum of CIDs associated with EBV-SMTs.

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“…A frequent functional genetic variant in the MMP1 promoter was reported to be associated with higher disease severity in RDEB due to an imbalance between type VII collagen synthesis and degradation . Finally, on a consanguineous background, co‐occurrence of EB and other genetic disorders leads to complex, apparently ‘new’ phenotypes …”

Section: Disease‐modifying Factorsmentioning

confidence: 99%

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility

et al. 2020

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Profound immunodeficiency with severe skin disease explained by concomitant novel CARMIL2 and PLEC1 loss-of-function mutations

Cited by 19 publications

References 11 publications

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

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

A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility

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