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

Clemente, N.; Boggio, E.; Gigliotti, C.L.; Orilieri, E.; Cappellano, G.; Toth, E. LU ; Valletti, P.A.; Santoro, C.; Quinti, Isabella and Pignata, C., et al. (2015) In Genes and Immunity 16(2). p.151-161
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... (More)
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. © 2015 Macmillan Publishers Limited. (Less)
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B cell activating factor receptor, caspase 9, complementary DNA, inducible T cell costimulator, perforin, transmembrane activator and CAML interactor, CASP9 protein, human, ICOS protein, human, TNFRSF13C protein, human, adult, apoptosis, Article, autoimmune lymphoproliferative syndrome, Burkitt lymphoma, common variable immunodeficiency, controlled study, down regulation, enzyme activation, enzyme activity, ex vivo study, female, gene mutation, genetic transfection, heterozygosity, human, human cell, immunoglobulin deficiency, in vitro gene transfer, lymphocyte proliferation, major clinical study, male, priority journal, protein expression, wild type, young adult, adolescent, biosynthesis, genetics, HEK293 cell line, immune deficiency, immunology, lymphoproliferative disease, metabolism, mutation, pedigree, Adolescent, Adult, Apoptosis, B-Cell Activation Factor Receptor, Caspase 9, Down-Regulation, HEK293 Cells, Humans, Immunologic Deficiency Syndromes, Inducible T-Cell Co-Stimulator Protein, Lymphoproliferative Disorders, Male, Mutation, Pedigree
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Genes and Immunity
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16
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2
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11 pages
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Nature Publishing Group
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  • scopus:84938557547
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1476-5470
DOI
10.1038/gene.2014.74
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English
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613b5f7a-2858-4ee8-82f1-0207d168780f
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https://www.scopus.com/inward/record.uri?eid=2-s2.0-84938557547&doi=10.1038%2fgene.2014.74&partnerID=40&md5=a2a0964a501fdd27c2c0d0e863d48add
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2017-04-18 11:15:49
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@article{613b5f7a-2858-4ee8-82f1-0207d168780f,
  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. © 2015 Macmillan Publishers Limited.},
  author       = {Clemente, N. and Boggio, E. and Gigliotti, C.L. and Orilieri, E. and Cappellano, G. and Toth, E. and Valletti, P.A. and Santoro, C. and Quinti, Isabella and Pignata, C. and Notarangelo, Luigi D and Dianzani, C. and Dianzani, I. and Ramenghi, Ugo and Dianzani, U. and Chiocchetti, Andreas},
  issn         = {1476-5470},
  keyword      = {B cell activating factor receptor,caspase 9,complementary DNA,inducible T cell costimulator,perforin,transmembrane activator and CAML interactor,CASP9 protein, human,ICOS protein, human,TNFRSF13C protein, human, adult,apoptosis,Article,autoimmune lymphoproliferative syndrome,Burkitt lymphoma,common variable immunodeficiency,controlled study,down regulation,enzyme activation,enzyme activity,ex vivo study,female,gene mutation,genetic transfection,heterozygosity,human,human cell,immunoglobulin deficiency,in vitro gene transfer,lymphocyte proliferation,major clinical study,male,priority journal,protein expression,wild type,young adult,adolescent,biosynthesis,genetics,HEK293 cell line,immune deficiency,immunology,lymphoproliferative disease,metabolism,mutation,pedigree, Adolescent,Adult,Apoptosis,B-Cell Activation Factor Receptor,Caspase 9,Down-Regulation,HEK293 Cells,Humans,Immunologic Deficiency Syndromes,Inducible T-Cell Co-Stimulator Protein,Lymphoproliferative Disorders,Male,Mutation,Pedigree},
  language     = {eng},
  number       = {2},
  pages        = {151--161},
  publisher    = {Nature Publishing Group},
  series       = {Genes and Immunity},
  title        = {A mutation in caspase-9 decreases the expression of BAFFR and ICOS in patients with immunodeficiency and lymphoproliferation},
  url          = {http://dx.doi.org/10.1038/gene.2014.74},
  volume       = {16},
  year         = {2015},
}