2. Academic Validation
  3. Study of the potential role of CASPASE-10 mutations in the development of autoimmune lymphoproliferative syndrome

Study of the potential role of CASPASE-10 mutations in the development of autoimmune lymphoproliferative syndrome

  • Cell Death Dis. 2024 May 4;15(5):315. doi: 10.1038/s41419-024-06679-6.
Filippo Consonni 1 2,  Solange Moreno # 3 4,  Blanca Vinuales Colell # 3 4,  Marie-Claude Stolzenberg 3 4,  Alicia Fernandes 5,  Mélanie Parisot 3 6,  Cécile Masson 3 7,  Nathalie Neveux 8 9,  Jérémie Rosain 3 10 11,  Sarah Bamberger 12,  Marie-Gabrielle Vigue 13,  Marion Malphettes 3 14,  Pierre Quartier 3 4 15,  Capucine Picard 3 11 15,  Frédéric Rieux-Laucat 3 4,  Aude Magerus 16 17
Affiliations

Affiliations

  • 1 Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
  • 2 Centre of Excellence, Division of Paediatric Oncology/Haematology, Meyer Children's Hospital IRCCS, Florence, Italy.
  • 3 University of Paris Cité, Paris, France.
  • 4 Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France.
  • 5 Plateforme Vecteurs Viraux et Transfert de Gènes, SFR Necker, INSERM US 24/CNRS UAR 3633, Faculté de santé Necker, Paris, France.
  • 6 Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UAR3633, Paris, France.
  • 7 Bioinformatics Core Facility, Paris-Cité University-Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, Paris, France.
  • 8 Laboratory of Biological Nutrition, EA 4466, Faculty of Pharmacy, Paris University, Paris, France.
  • 9 Clinical Chemistry Department, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Paris, France.
  • 10 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
  • 11 Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
  • 12 Pediatrics Gastroenterology and Nutrition, Robert-Debré Hospital, Paris, France.
  • 13 Pediatrics, Infectiology, Rhumatology, Hôpital Arnaud-de-Villeneuve, CHRU de Montpellier, Montpellier, France.
  • 14 Department of Clinical Immunology, Hôpital Saint-Louis, AP-HP, Paris, France.
  • 15 Pediatric immuno-hematology and rheumatology department, Necker-Enfants Malades Hospital, Assistance publique - Hôpitaux de Paris, Paris, France.
  • 16 University of Paris Cité, Paris, France. [email protected].
  • 17 Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France. [email protected].
  • # Contributed equally.
PMID: 38704374 DOI: 10.1038/s41419-024-06679-6
Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a primary disorder of lymphocyte homeostasis, leading to chronic lymphoproliferation, autoimmune cytopenia, and increased risk of lymphoma. The genetic landscape of ALPS includes mutations in FAS, FASLG, and FADD, all associated with Apoptosis deficiency, while the role of CASP10 defect in the disease remains debated. In this study, we aimed to assess the impact of CASP10 variants on ALPS pathogenesis. We benefit from thousands of genetic analysis datasets performed in our Institute's genetic platform to identify individuals carrying CASP10 variants previously suspected to be involved in ALPS outcome: p.C401LfsX15, p.V410I and p.Y446C, both at heterozygous and homozygous state. Clinical and laboratory features of the six included subjects were variable but not consistent with ALPS. Two individuals were healthy. Comprehensive analyses of CASP10 protein expression and FAS-mediated Apoptosis were conducted and compared to healthy controls and ALPS patients with FAS mutations. Missense CASP10 variants (p.V410I and p.Y446C), which are common in the general population, did not disrupt CASP10 expression, nor FAS-mediated Apoptosis. In contrast, homozygous p.C401LfsX15 CASP10 variant lead to a complete abolished CASP10 expression but had no impact on FAS-mediated Apoptosis function. At heterozygous state, this p.C401LfsX15 variant lead to a reduced CASP10 protein levels but remained associated with a normal FAS-mediated Apoptosis function. These findings demonstrate that Caspase 10 is dispensable for FAS-mediated Apoptosis. In consequences, CASP10 defect unlikely contribute to ALPS pathogenesis, since they did not result in an impairment of FAS-mediated Apoptosis nor in clinical features of ALPS in human. Moreover, the absence of FAS expression up-regulation in subjects with CASP10 variants rule out any compensatory mechanisms possibly involved in the normal Apoptosis function observed. In conclusion, this study challenges the notion that CASP10 variants contribute to the development of ALPS.

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