Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome
Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome
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DOI：
10.1097/mpg.0000000000001262
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发表时间：
2017-03-01
影响因子：
2.9
通讯作者：
Cerf-Bensussan, Nadine
中科院分区：
文献类型：
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作者：
Charbit-Henrion, Fabienne;Jeverica, Anja K.;Cerf-Bensussan, Nadine
目的：早发性炎症性肠病可由多种罕见的孟德尔疾病引起。早期分子诊断对于确定治疗和提高预期寿命至关重要。在这里，我们的目的是在定义的免疫缺陷多内分泌病和肠病X-连锁（IPEX）样疾病的机制结合严重的免疫缺陷，在2个兄弟姐妹出生的远亲parents.Methods：全外显子组测序进行血液提取的基因组DNA从2个受影响的儿童和他们的父母的基因组平台上的Institut IMAGINE。使用内部软件PolyWeb鉴定候选基因突变，并通过桑格测序确认。蛋白质表达通过western blot测定。流式细胞术被用来评估淋巴细胞表型和核因子-κ B（NF-B）的激活在诊断和治疗后的造血干细胞transplantation.Results：我们确定了一个纯合的错义突变的粘膜相关淋巴组织淋巴瘤易位1基因（MALT 1），这排除了蛋白质的表达突变的后果。与MALT 1的已知功能一致，NF-B依赖性淋巴细胞活化严重受损。此外，叉头盒P3（FOXP 3）调节性T细胞急剧减少，这是IPEX样表型的原因。在鉴定出突变后，两个孩子都接受了造血干细胞移植，这使得临床完全康复。移植后6个月和12个月的免疫学检查显示正常的NF-B活化和调节性T细胞frequency.Conclusions：沿着FOXP 3、白细胞介素2受体α链（IL 2 RA）和细胞毒性T淋巴细胞蛋白4前体（CTLA-4）突变，MALT 1缺陷现在应该被认为是IPEX样综合征相关免疫缺陷的可能原因，可以通过造血干细胞移植治愈。
Objective: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.Methods: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-B) 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-B-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-B activation and correction of regulatory T cells frequency.Conclusions: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.