A human immunodeficiency syndrome caused by mutations in CARMIL2

Nat Commun. 2017 Jan 23;8:14209. doi: 10.1038/ncomms14209.

T Schober ¹, T Magg ¹, M Laschinger ², M Rohlfs ¹, N D Linhares ³, J Puchalka ¹, T Weisser ², K Fehlner ², J Mautner ⁴ ⁵ ⁶, C Walz ⁷, K Hussein ⁸, G Jaeger ⁹, B Kammer ¹, I Schmid ¹, M Bahia ¹⁰, S D Pena ³, U Behrends ⁴ ⁵ ⁶, B H Belohradsky ¹, C Klein ¹ ⁶, F Hauck ¹ ⁶

Affiliations

1 Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Lindwurmstrasse 4, D-80337 Munich, Germany.
2 Department of Surgery, Technische Universität München (TUM), Ismaninger Strasse 22, D-81675 Munich, Germany.
3 Laboratory of Clinical Genomics, Federal University of Minas Gerais, 190 Professor Alfredo Balena Avenida, Belo Horizonte 30130-100, Brazil.
4 Research Unit Gene Vectors, Helmholtz Zentrum München (HMGU)-German Research Center for Environmental Health, Marchioninistrasse 25, D-81377 Munich, Germany.
5 Children's Hospital, Technische Universität München (TUM), Munich D-80804, Germany.
6 German Centre for Infection Research (DZIF), Trogerstrasse 30, D-81675 Munich, Germany.
7 Institute of Pathology, Ludwig-Maximilians-Universität (LMU), Thalkirchner Strasse 36, D-80337 Munich, Germany.
8 Institute of Pathology, Hannover Medical School (MHH), Carl-Neuberg-Strasse 1, D-30625 Hanover, Germany.
9 Department of Diagnostic Virology, Max von Pettenkofer-Institute, Ludwig-Maximilians-Universität (LMU), Pettenkoferstrasse 9a, D-80336 Munich, Germany.
10 Department of Pediatric Gastroenterology, Federal University of Minas Gerais, 110 Prof. Alfredo Balena Avenida, Belo Horizonte 30130-100, Brazil.

PMID: 28112205 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.

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