Evolution and long‐term outcomes of combined immunodeficiency due to CARMIL2 deficiency

Abstract

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

Of Mycelium and Men: Inherent Human Susceptibility to Fungal Diseases

“…Intriguingly, mutations in T-cell-co-stimulatory molecules other than CD40L, notably those disrupting CD28/CD80 or CD86 (via recessive mutations in CD28 [ 197 ] or its essential signaling partners, RLTPR (also known as CARMIL2) [ 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 ] or CARD11 [ 206 , 207 , 208 , 209 , 210 ]) or ICOS/ICOSL interactions (via recessive mutations in either ICOS [ 211 , 212 , 213 , 214 , 215 , 216 ] or ICOSL [ 217 , 218 ]), have not been reported in association with TDEF. Whether this reflects stochasticity (i.e., a lack of exposure from geographic restriction among those with these rare diseases), or whether sufficient pathologic exposure has indeed occurred, but the respective molecules and T cell activation pathways are not critical for TDF host defenses, are questions that remain to be determined.…”

A Novel CARMIL2 Immunodeficiency Identified in a Subset of Cavalier King Charles Spaniels with Pneumocystis and Bordetella Pneumonia

“…A nonsense variant in exon 11 of CARMIL2 (CanFam3.1 CFA5 g.81801920G>A, Dog10K_Boxer_Tasha CFA5 g.81791628, UniProt A0A8I3NGS3 p.R291*) was identified as the likely pathogenic variant given the role of the gene in immune function and previous reports in humans potentially linking CARMIL2 variants with PCP [ 29 , 30 ]. CARMIL2 variants reported to cause PI in human patients result in significantly reduced to undetectable levels of protein expression [ 29 , 30 , 31 ]. The canine CARMIL2 protein consists of 1394 amino acids; the p.R291* variant identified here results in a loss of 79% of the protein sequence.…”

Comparing the levels of CTLA‐4‐dependent biological defects in patients with LRBA deficiency and CTLA‐4 insufficiency

“…Peripheral lymphocyte subset analyses and intracellular protein staining were performed by flow cytometry as described previously 13,18,20 and compared with age-matched healthy reference values. 21 The FOXP3 and CTLA-4 expressions were evaluated at diagnosis before starting abatacept treatment.…”