title: Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome.
abstract: Early-onset inflammatory bowel diseases can result from a wide spectrum of rare mendelian disorders. Early molecular diagnosis is crucial in defining treatment and in improving life expectancy. Herein we aimed at defining the mechanism of an immunodeficiency-polyendrocrinopathy and enteropathy-X-linked (IPEX)-like disease combined with a severe immunodeficiency in 2 siblings born from distantly related parents.
  
  
  
  Whole exome sequencing was performed on blood-extracted genomic DNA from the 2 affected children and their parents on the genomic platform of Institut IMAGINE. Candidate gene mutation was identified using the in-house software PolyWeb and confirmed by Sanger sequencing. Protein expression was determined by western blot. Flow cytometry was used to assess consequences of the mutation on lymphocyte phenotype and nuclear factor-kappa B (NF-κB) activation at diagnosis and after treatment by hematopoietic stem cell transplantation.
  
  
  
  We identified a homozygous missense mutation in mucosa-associated lymphoid tissue lymphoma translocation 1 gene (MALT1), which precluded protein expression. In keeping with the known function of MALT1, NF-κB-dependent lymphocyte activation was severely impaired. Moreover, there was a drastic reduction in Forkhead box P3 (FOXP3) regulatory T cells accounting for the IPEX-like phenotype. Following identification of the mutation, both children received hematopoietic stem cell transplantation, which permitted full clinical recovery. Immunological workup at 6 and 12 months after transplantation showed normal NF-κB activation and correction of regulatory T cells frequency.
  
  
  
  Along with FOXP3, interleukin 2 receptor alpha chain (IL2RA), and cytotoxic T-lymphocyte protein 4 precursor (CTLA-4) mutations, MALT1 deficiency should now be considered as a possible cause of IPEX-like syndrome associated with immunodeficiency that can be cured by hematopoietic stem cell transplantation.
authors.affiliation: *INSERM, UMR1163, Laboratory of Intestinal Immunity †Université Paris Descartes-Sorbonne Paris Cité and Institut IMAGINE ‡Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Department of Pediatric Gastroenterology, Paris §GENIUS Group (GENetically and/or ImmUne mediated enteropathieS) From ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) ||Department of Allergology, Rheumatology and Clinical Immunology ¶Department of Haemato-oncology, University Children's Hospital, University Medical Center, Ljubljana, Slovenia #Institut de Minéralogie, de Physique des Matériaux, et de Cosmochimie, Sorbonne Universités-UMR CNRS 7590, UPMC Université Paris 6, Muséum National d'Histoire Naturelle, IRD UMR 206, IUC **Bioinformatics Platform, Université Paris-Descartes-Paris Sorbonne Centre and Institut IMAGINE ††Genomic platform, Institut IMAGINE, Paris, France ‡‡Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital §§Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia ||||INSERM, UMR1163, Immunogenetics of Pediatric Autoimmunity, Paris, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Charbit-Henrion
authors.forename: Anja K
authors.initials: AK
authors.lastname: Jeverica
authors.forename: Bernadette
authors.initials: B
authors.lastname: Bègue
authors.forename: Gasper
authors.initials: G
authors.lastname: Markelj
authors.forename: Marianna
authors.initials: M
authors.lastname: Parlato
authors.forename: Simona Lucija
authors.initials: SL
authors.lastname: Avčin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.forename: Marc
authors.initials: M
authors.lastname: Bras
authors.forename: Mélanie
authors.initials: M
authors.lastname: Parisot
authors.forename: Janez
authors.initials: J
authors.lastname: Jazbec
authors.forename: Matjaz
authors.initials: M
authors.lastname: Homan
authors.forename: Alojz
authors.initials: A
authors.lastname: Ihan
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Stolzenberg
authors.forename: Frank M
authors.initials: FM
authors.lastname: Ruemmele
authors.forename: Tadej
authors.initials: T
authors.lastname: Avčin
authors.forename: Nadine
authors.initials: N
authors.lastname: Cerf-Bensussan
mesh_terms: D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D003967:Diarrhea / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics*; D005819:Genetic Markers; D006720:Homozygote; D006801:Humans; D007154:Immune System Diseases / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D008297:Male; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / Q000172:deficiency* / Q000235:genetics; D020125:Mutation, Missense; D035781:Siblings
chemical_list: D005819:Genetic Markers; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein