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Schober, T.; Magg, T.; Laschinger, M.; Rohlfs, M.; Linhares, N. D.; Puchalka, J.; Weisser, T.; Fehlner, K.; Mautner, J.; Walz, C.; Hussein, K.; Jäger, G.; Kammer, B.; Schmid, I.; Bahia, M.; Pena, S. D.; Behrends, U.; Belohradsky, B. H.; Klein, C. and Hauck, F. (2017): A human immunodeficiency syndrome caused by mutations in CARMIL2. In: Nature Communications, Vol. 8, 14209 [PDF, 5MB]


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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