The capping protein regulator and myosin 1 linker 2 (CARMIL2) deficiency is an autosomal recessive inborn error of immunity (IEI) leading to combined T-cell, B-cell, and NK cell defects. 1,2 CARMIL2, also known as RGD motif, leucine-rich repeats, tropomodulin domain, and proline-rich containing protein (RLTPR), is a member of the CARMIL family. This family consists of three paralogous genes (CARMIL1, CARMIL2, and CARMIL3), producing multidomain proteins with high sequence homology. They contain an N-terminal pleckstrin homology (PH) domain, a leucine-rich repeat (LRR) domain, a homodimerization domain (HD), and a C-terminal domain including a capping protein binding region (CBR) and a proline-rich region (PRR).While all CARMILs have a capacity to bind to the capping proteins and regulate actin assembly, each protein also has a unique cellular function. 3 CARMIL1 activates the Trio-Rac1 pathway to enhance Arp2/3-mediated actin polymerization, 4,5 whereas CARMIL2 binds to cellular membranes via vimentin, and activates T cells by ligating CD28 and CARMA1 to mediate NFk B signaling. 6,7 Mice expressing mutated Carmil2 gene are not able to conduct CD28-mediated activation of its effector protein kinase C theta (PKCθ), abrogating effector memory CD4 + T and regulatory T cells (Treg) development. 7,8 CARMIL2 is also necessary for invadopodia formation, cell polarity, lamellipodial assembly, membrane ruffling, macropinocytosis, and cell migration. 3 The CARMIL3 is expressed mainly in the brain and spinal cord, and identified as oncofetal gene; however, recently, it was demonstrated as essential regulator of the proinflammatory cytokines in macrophages. 3,9 The human CARMIL2 gene was originally identified by Matsuzaka et al. and shown to be downregulated in affected skin cells of psoriasis vulgaris patients. 10 The CARMIL2 protein is expressed in the cytoplasm, especially in the skin, lymphoid tissue, and gastrointestinal system, and was demonstrated to play a role in wound healing. 3 So far, fewer than 40 cases of CARMIL2 deficiency have been reported worldwide. Patients with CARMIL2 deficiency present with a broad range of symptoms, including cutaneous and respiratory allergies mainly characterized by eczematous lesions, early-onset

Objective: Mutations in IKZF1, which encodes Ikaros family zinc finger 1 (IKAROS) transcription factor, are associated with recurrent infections, cytopenia, autoimmune diseases, and hematologic malignancies. Diverse clinical phenotypes resulting from IKZF1 mutations include pulmonary fungal infections, cytopenia, autoimmune hemolytic anemia (AIHA), and malignancies. In this study, we aimed to assess the DNA-binding ability and pericentromeric (PC) localization of a variant of IKZF discovered in a patient. Materials and Methods: DNA-binding ability of a pathogenic IKZF variant was tested using electrophoretic mobility shift assay and PC localization of the variant was assessed by immunofluorescent microscopy in NIH3T3 cells. Results: Clinical features of a 3-month-old male infant who underwent hematopoietic stem cell transplantation because of an IKZF1 mutation-associated common variable immunodeficiency, AIHA, and pancytopenia are described. DNA studies revealed a heterozygous missense variant (IKZF1 NM_006060 c.427C>T; p.R143W). Cotransfection studies revealed that mutant R143W has a partial dominant-negative effect over PC targeting and DNA binding. Conclusions: IKZF1 mutation must be kept in mind if neonatal AIHA, common variable immunodeficiency, and pancytopenia are observed.

Insu cient dietary folate intake, hereditary malabsorption, or defects in folate metabolism may lead to combined immunode ciency (CID). Although loss of function mutations in the major intestinal folate transporter PCFT/SLC46A1 was shown to be associated with CID, the evidence for pathogenic variants of RFC/SLC19A1 resulting in immunode ciency was lacking. We report two cousins carrying a homozygous pathogenic variant c.1042G>A, resulting in p.G348R substitution who showed symptoms of immunode ciency associated with defects of folate metabolism. SLC19A1 expression by peripheral blood mononuclear cells (PBMC) was quanti ed by real-time qPCR and immunostaining. T cell proliferation, methotrexate resistance, NK cell cytotoxicity, Treg cells and cytokine production by T cells were examined by ow cytometric assays. Patients were treated with and bene ted from folinic acid (FA). Studies revealed normal NK cell cytotoxicity, Treg cell counts, and naive-memory T cell percentages. Although SLC19A1 mRNA and protein expression were unaltered, remarkably, mitogen induced-T cell proliferation was signi cantly reduced at sub-and supraoptimal folic acid concentrations. In addition, patients' PBMCs were resistant to methotrexate-induced apoptosis supporting a functionally defective SLC19A1.This study presents the second pathogenic SLC19A1 variant in the literature, providing the rst experimental evidence that loss of function mutations in SLC19A1 may present with symptoms of immunode ciency.

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Hemophilia A, B are X-linked recessive bleeding disorder that typically results from a deficiency of clotting factor VIII (FVIII) and factor IX (FIX). The severity of the disease is determined according to the FVIII and FIX levels. Hemophilia A and B have similar symptoms and are both characterized by bleeding, particularly in large joints such as ankles, knees, elbows. Recurrent bleeding in joints eventually causes progressive hemophilic arthropathy. Life-threatening hemorrhages may occur rarely. Treatment of hemophilia has improved significantly in recent years with clotting factor concentrates. The average life expectancy was