FAS-mediated apoptosis impairment in patients with ALPS/ALPS-like phenotype carrying variants on CASP10 gene

Maurizio Miano, Enrico Cappelli, Agnese Pezzulla, Roberta Venè, Alice Grossi, Paola Terranova, Elena Palmisani, Rosario Maggiore, Daniela Guardo, Tiziana Lanza, Michaela Calvillo, Concetta Micalizzi, Filomena Pierri, Chiara Vernarecci, Andrea Beccaria, Fabio Corsolini, Marina Lanciotti, Giovanna Russo, Isabella Ceccherini, Carlo DufourFrancesca Fioredda

Research output: Contribution to journalArticle

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10-mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS-like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS-ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS-like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype.

Original languageEnglish
Pages (from-to)502-508
Number of pages7
JournalBritish Journal of Haematology
Volume187
Issue number4
DOIs
Publication statusPublished - 2019

Fingerprint

Autoimmune Lymphoproliferative Syndrome
Apoptosis
Phenotype
Genes
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Mutation
Homozygote
Autoimmunity
Virulence
Cell Death
Lymphocytes
Ligands

Keywords

  • apoptosis
  • autoimmune diseases
  • autoimmune lymphoproliferative syndrome
  • caspases
  • immune-dysregulation

ASJC Scopus subject areas

  • Hematology

Cite this

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title = "FAS-mediated apoptosis impairment in patients with ALPS/ALPS-like phenotype carrying variants on CASP10 gene",
abstract = "Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10-mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS-like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS-ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS-like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype.",
keywords = "apoptosis, autoimmune diseases, autoimmune lymphoproliferative syndrome, caspases, immune-dysregulation",
author = "Maurizio Miano and Enrico Cappelli and Agnese Pezzulla and Roberta Ven{\`e} and Alice Grossi and Paola Terranova and Elena Palmisani and Rosario Maggiore and Daniela Guardo and Tiziana Lanza and Michaela Calvillo and Concetta Micalizzi and Filomena Pierri and Chiara Vernarecci and Andrea Beccaria and Fabio Corsolini and Marina Lanciotti and Giovanna Russo and Isabella Ceccherini and Carlo Dufour and Francesca Fioredda",
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journal = "British Journal of Haematology",
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TY - JOUR

T1 - FAS-mediated apoptosis impairment in patients with ALPS/ALPS-like phenotype carrying variants on CASP10 gene

AU - Miano, Maurizio

AU - Cappelli, Enrico

AU - Pezzulla, Agnese

AU - Venè, Roberta

AU - Grossi, Alice

AU - Terranova, Paola

AU - Palmisani, Elena

AU - Maggiore, Rosario

AU - Guardo, Daniela

AU - Lanza, Tiziana

AU - Calvillo, Michaela

AU - Micalizzi, Concetta

AU - Pierri, Filomena

AU - Vernarecci, Chiara

AU - Beccaria, Andrea

AU - Corsolini, Fabio

AU - Lanciotti, Marina

AU - Russo, Giovanna

AU - Ceccherini, Isabella

AU - Dufour, Carlo

AU - Fioredda, Francesca

PY - 2019

Y1 - 2019

N2 - Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10-mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS-like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS-ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS-like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype.

AB - Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10-mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS-like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS-ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS-like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype.

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KW - autoimmune diseases

KW - autoimmune lymphoproliferative syndrome

KW - caspases

KW - immune-dysregulation

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