A human immunodeficiency syndrome caused by mutations in CARMIL2

Tilmann Schober ,Tanja Weißer ,Josef Mautner ,Bernd H Belohradsky ,Christoph Klein ,Jacek Puchałka ,Karin Fehlner ,Irene Schmid ,Melanie Laschinger ,Natália Duarte Linhares ,Thomas Magg ,Gundula Jaeger ,Meino Rohlfs ,Mirleide Chaar Bahia ,Birgit Kammer ,Kais Hussein ,Sérgio D.j Pena ,Christoph Walz ,Uta Behrends ,Fabian Hauck

doi:10.1038/ncomms14209

Abstract

Human T-cell function is dependent on T-cell antigen receptor (TCR) and co-signalling as evidenced by immunodeficiencies affecting TCR-dependent signalling pathways. Here, we show four human patients with EBV+ disseminated smooth muscle tumours that carry two homozygous loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and myosin 1 linker 2. These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function, as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders. Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics.

Highlights

Human T-cell function is dependent on T-cell antigen receptor (TCR) and co-signalling as evidenced by immunodeficiencies affecting TCR-dependent signalling pathways
Liver and brain Epstein–Barr virus (EBV) þ smooth muscle tumours (SMT) were excised and the patient was treated by an individualized chemotherapy regimen with oral cyclophosphamide
We here describe a novel human primary immunodeficiency disorders (PID) caused by autosomal recessive mutations in CARMIL2 that abrogated protein expression

Summary

Introduction

Human T-cell function is dependent on T-cell antigen receptor (TCR) and co-signalling as evidenced by immunodeficiencies affecting TCR-dependent signalling pathways. We show four human patients with EBV þ disseminated smooth muscle tumours that carry two homozygous loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and myosin 1 linker 2. These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function, as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders. TCR-dependent signalling is one of the most studied signalling cascades, knowledge of CD28 co-signalling is incomplete[8,9]

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Conclusion