Avtor/Urednik		Charbit-Henrion, Fabienne; Koren, Anja; Bègue, Bernadette; Markelj, Gašper; Parlato, Marianna; Avčin, Simona; Jazbec, Janez; Homan, Matjaž; Ihan, Alojz; Avčin, Tadej
Naslov		Deficiency in mucosa associated lymphoid tissue lymphoma translocation 1 (MALT1)
Tip		članek
Leto izdaje		2016
ISSN		0277-2116 - Journal of pediatric gastroenterology and nutrition
Jezik		eng
Abstrakt		Objective: Early onset inflammatory bowel diseases can result from a wide spectrum of rare Mendelian disorders. Early molecular diagnosis is crucial to define treatment and improve life expectancy. Herein we aimed at defining the mechanism of an IPEX-like disease (Immunodeficiency-Polyendrocrinopathy and Enteropathy-X-linked) combined with a severe immunodeficiency in two siblings born from distantly related parents. Methods: Whole exome sequencing was performed on blood-extracted genomic DNA from the two 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-KB) activation at diagnosis and after treatment by hematopoietic stem cell transplantation. Results: 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-KB-dependent lymphocyte activation was severely impaired. Moreover there was a drastic reduction in FOXP3 regulatory T cells (Treg) accounting for the IPEX-like phenotype. Following identification of the mutation, both children received hematopoietic stem cell transplantation, which permitted full clinical recovery. Immunological work-up at 6 and 12 months after transplantation showed normal NF-KB activation and correction of Treg frequency. Conclusion: Along with FOXP3, IL2RA and 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.
Proste vsebinske oznake		inflammatory bowel diseases mucosa mutation vnetne črevesne bolezni sluznica mutacije