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A mutation in caspase-9 decreases the expression of BAFFR and ICOS in patients with immunodeficiency and lymphoproliferation

Genes & Immunity volume 16, pages 151–161 (2015)Cite this article

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Abstract

Lymphocyte apoptosis is mainly induced by either death receptor-dependent activation of caspase-8 or mitochondria-dependent activation of caspase-9. Mutations in caspase-8 lead to autoimmunity/lymphoproliferation and immunodeficiency. This work describes a heterozygous H237P mutation in caspase-9 that can lead to similar disorders. H237P mutation was detected in two patients: Pt1 with autoimmunity/lymphoproliferation, severe hypogammaglobulinemia and Pt2 with mild hypogammaglobulinemia and Burkitt lymphoma. Their lymphocytes displayed defective caspase-9 activity and decreased apoptotic and activation responses. Transfection experiments showed that mutant caspase-9 display defective enzyme and proapoptotic activities and a dominant-negative effect on wild-type caspase-9. Ex vivo analysis of the patients’ lymphocytes and in vitro transfection experiments showed that the expression of mutant caspase-9 correlated with a downregulation of BAFFR (B-cell-activating factor belonging to the TNF family (BAFF) receptor) in B cells and ICOS (inducible T-cell costimulator) in T cells. Both patients carried a second inherited heterozygous mutation missing in the relatives carrying H237P: Pt1 in the transmembrane activator and CAML interactor (TACI) gene (S144X) and Pt2 in the perforin (PRF1) gene (N252S). Both mutations have been previously associated with immunodeficiencies in homozygosis or compound heterozygosis. Taken together, these data suggest that caspase-9 mutations may predispose to immunodeficiency by cooperating with other genetic factors, possibly by downregulating the expression of BAFFR and ICOS.

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Acknowledgements

This work was partially supported by Associazione Italiana Ricerca sul Cancro (AIRC, Milan; funding number #14430), Fondazione Cariplo (Milan), Fondazione Italiana Sclerosi Multipla (FISM, Rome), Compagnia di San Paolo (Turin), Fondazione Cassa di Risparmio di Cuneo (Cuneo), Regione Piemonte (Turin) and Associazione ‘Amici di Jean’ (Turin). We thank Dr Michael Lenardo and Dr Frederic Rieux-Laucat for providing some patients’ DNA.

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Authors and Affiliations

  1. Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont ‘A Avogadro’, Novara, Italy

    N Clemente, E Boggio, C L Gigliotti, E Orilieri, G Cappellano, E Toth, P A Valletti, C Santoro, I Dianzani, U Dianzani & A Chiocchetti

  2. Department of Clinical Immunology, University of Rome ‘La Sapienza’, Rome, Italy

    I Quinti

  3. Department of Pediatrics, ‘Federico II’ University, Naples, Italy

    C Pignata

  4. Division of Immunology, Children’s Hospital, Harvard Medical School, Boston, MA, USA

    L D Notarangelo

  5. Department of Drug Science and Technology, University of Turin, Turin, Italy

    C Dianzani

  6. Department of Pediatrics, University of Turin, Turin, Italy

    U Ramenghi

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Clemente, N., Boggio, E., Gigliotti, C. et al. A mutation in caspase-9 decreases the expression of BAFFR and ICOS in patients with immunodeficiency and lymphoproliferation. Genes Immun 16, 151–161 (2015). https://doi.org/10.1038/gene.2014.74

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