Journal Article

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

Prince, Benjamin T., Cripe, Timothy P., Yonkof, Jennifer R., Mangray, Shamlal, Varga, Elizabeth, Abraham, Roshini S., Alshahrani, Mohammad, Rangarajan, Hemalatha G., Gupta, Ajay, Rueda, Cesar M.

2020

Overview

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 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 and expand the genotypic and phenotypic spectrum of CIDs associated with EBV-SMTs.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Asthma / CARMIL2 deficiency / Case reports / CD25 antigen / CD28 antigen / CD28 Antigens - metabolism / CD3 antigen / CD4 antigen / CD8 antigen / Cell growth / Cell proliferation / Cells, Cultured / Cloning / Cytoskeleton / Cytoskeleton - metabolism / Dermatitis / Diarrhea / DOCK8 deficiency / EBV-associated smooth muscle tumor / Epstein-Barr virus / Epstein-Barr Virus Infections - genetics / Family medical history / Flow cytometry / Foxp3 protein / Genotype & phenotype / Herpesvirus 4, Human - physiology / Humans / immune dysregulation / Immune system / Immunodeficiency / Immunological memory / Immunology / Immunoregulation / Inflammatory bowel disease / Kinases / Lungs / Lymphocyte Activation / Lymphocytes / Lymphocytes B / Lymphocytes T / Male / Memory cells / Microfilament Proteins - genetics / Pathogenicity / Pedigree / Phenotypes / Pneumonia / primary immunodeficiencies / Primary Immunodeficiency Diseases - genetics / Protein expression / Proteins / RLTPR / Saudi Arabia / Siblings / Smooth muscle / Smooth Muscle Tumor / Steroids / T-Lymphocytes - physiology / Transplants & implants / Tumors