PDF(Pubmed)
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.
摘要：
自身免疫性淋巴细胞增生综合征（ALPS）是淋巴细胞稳态的原发性疾病，导致慢性淋巴增生，自身免疫性血细胞减少症，和淋巴瘤的风险增加。ALPS的遗传景观包括FAS的突变，FASLG,和FADD,都与细胞凋亡缺乏有关，而CASP10缺陷在该疾病中的作用仍存在争议。在这项研究中,我们旨在评估CASP10变异体对ALPS发病机制的影响.我们受益于在我们研究所的遗传平台上进行的数千个遗传分析数据集，以识别携带CASP10变异体的个体，这些变异体以前被怀疑参与ALPS结果：p.C401LfsX15，p.V410I和p.Y446C，处于杂合和纯合状态。六名纳入受试者的临床和实验室特征是可变的，但与ALPS不一致。两个人是健康的。对CASP10蛋白表达和FAS介导的细胞凋亡进行了综合分析，并与健康对照和具有FAS突变的ALPS患者进行了比较。错觉CASP10变体（第V410I和p.Y446C)，这在普通人群中很常见，没有破坏CASP10的表达，也不是FAS介导的细胞凋亡。相比之下,纯合p.C401LfsX15CASP10变体导致CASP10表达完全消除，但对FAS介导的凋亡功能没有影响。在杂合状态下，这种p.C401LfsX15变体导致CASP10蛋白水平降低,但仍与正常的FAS介导的细胞凋亡功能相关.这些发现证明CASPASE10对于FAS介导的细胞凋亡是不必要的。在后果中，CASP10缺陷不太可能导致ALPS发病机制，因为它们不会导致FAS介导的细胞凋亡受损，也不会导致人ALPS的临床特征。此外，CASP10变异体受试者中FAS表达上调的缺失排除了任何可能参与观察到的正常凋亡功能的代偿机制。总之,这项研究挑战了CASP10变异体有助于ALPS发展的观点.
