title: A mutation in caspase-9 decreases the expression of BAFFR and ICOS in patients with immunodeficiency and lymphoproliferation.
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.
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont 'A Avogadro', Novara, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Clemente
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont 'A Avogadro', Novara, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Boggio
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont 'A Avogadro', Novara, Italy.
authors.forename: C L
authors.initials: CL
authors.lastname: Gigliotti
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont 'A Avogadro', Novara, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Orilieri
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont 'A Avogadro', Novara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cappellano
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont 'A Avogadro', Novara, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Toth
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont 'A Avogadro', Novara, Italy.
authors.forename: P A
authors.initials: PA
authors.lastname: Valletti
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont 'A Avogadro', Novara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Santoro
authors.affiliation: Department of Clinical Immunology, University of Rome 'La Sapienza', Rome, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Quinti
authors.affiliation: Department of Pediatrics, 'Federico II' University, Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Pignata
authors.affiliation: Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Department of Drug Science and Technology, University of Turin, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Dianzani
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont 'A Avogadro', Novara, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Dianzani
authors.affiliation: Department of Pediatrics, University of Turin, Turin, Italy.
authors.forename: U
authors.initials: U
authors.lastname: Ramenghi
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont 'A Avogadro', Novara, Italy.
authors.forename: U
authors.initials: U
authors.lastname: Dianzani
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont 'A Avogadro', Novara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Chiocchetti
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D053265:B-Cell Activation Factor Receptor / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D053453:Caspase 9 / Q000235:genetics* / Q000276:immunology; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D060889:Inducible T-Cell Co-Stimulator Protein / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree
chemical_list: D053265:B-Cell Activation Factor Receptor; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; C435926:TNFRSF13C protein, human; C506433:CASP9 protein, human; D053453:Caspase 9