STXBP2-R190C Variant in a Patient With Neonatal Hemophagocytic Lymphohistiocytosis (HLH) and G6PD Deficiency Reveals a Critical Role of STXBP2 Domain 2 on Granule Exocytosis.
STXBP2-R190C Variant in a Patient With Neonatal Hemophagocytic Lymphohistiocytosis (HLH) and G6PD Deficiency Reveals a Critical Role of STXBP2 Domain 2 on Granule Exocytosis.
复制标题
DOI：
10.3389/fimmu.2020.545414
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
Giraudo CG
中科院分区：
文献类型：
--
作者：
Benavides N;Spessott WA;Sanmillan ML;Vargas M;Livingston MS;Erickson N;Pozos TC;McCormick ME;Scharrig E;Messinger YH;Giraudo CG
新生儿噬血细胞性淋巴组织细胞增生症（HLH）是一种医疗紧急情况，可以与显着的发病率和死亡率。通常这些患者存在家族性HLH（f-HLH），其由干扰细胞毒性T淋巴细胞（CTL）和自然杀伤细胞的细胞溶解途径的基因突变引起。在这里，我们描述了一个男性新生儿谁符合HLH诊断标准，提出了深刻的胆汁淤积，并进行了母系遗传的杂合突变的syntaxin结合蛋白-2（STXBP 2，c.568C>T（p.Arg190Cys））除了一个严重的致病性变异的葡萄糖6-磷酸脱氢酶（G6 PD，半合子c.1153T>C（Cys 385 Arg））。虽然STXBP 2基因突变与f-HLH 5型相关，但该患者中鉴定的p.Arg190Cys突变的临床和生物学相关性尚不确定。为了评估其在疾病发病机制中的作用，我们进行了功能测定和生化及显微镜研究。我们发现p.Arg190Cys突变并没有改变STXBP 2或STX 11的表达或亚细胞定位，也没有损害STXBP 2/STX 11的相互作用。相比之下，突变的蛋白质强制表达到正常的CTL强烈抑制脱粒和减少的细胞溶解活性胜过内源性野生型STXBP 2的作用。有趣的是，精氨酸190位于STXBP 2的结构保守区域，其中已鉴定出其他f-HLH-5突变。总的来说，数据强烈表明STXBP 2-R190 C是一种有害变体，它可能通过稳定STXBP 2/STX 11复合物与其他仍未知因素（例如膜表面或Munc 13 -4蛋白）之间的非生产性相互作用，以显性负作用方式发挥作用，从而损害细胞溶解颗粒的释放。除了STXBP 2-R190 C对f-HLH的贡献外，伴随的G6 PD突变可能使临床症状复杂化;然而，G6 PD缺陷在我们患者中对HLH的贡献程度仍不清楚。
Neonatal hemophagocytic lymphohistiocytosis (HLH) is a medical emergency that can be associated with significant morbidity and mortality. Often these patients present with familial HLH (f-HLH), which is caused by gene mutations interfering with the cytolytic pathway of cytotoxic T-lymphocytes (CTLs) and natural killer cells. Here we describe a male newborn who met the HLH diagnostic criteria, presented with profound cholestasis, and carried a maternally inherited heterozygous mutation in syntaxin-binding protein-2 [STXBP2, c.568C>T (p.Arg190Cys)] in addition to a severe pathogenic variant in glucose 6-phosphate dehydrogenase [G6PD, hemizygous c.1153T>C (Cys385Arg)]. Although mutations in STXBP2 gene are associated with f-HLH type 5, the clinical and biological relevance of the p.Arg190Cys mutation identified in this patient was uncertain. To assess its role in disease pathogenesis, we performed functional assays and biochemical and microscopic studies. We found that p.Arg190Cys mutation did not alter the expression or subcellular localization of STXBP2 or STX11, neither impaired the STXBP2/STX11 interaction. In contrast, forced expression of the mutated protein into normal CTLs strongly inhibited degranulation and reduced the cytolytic activity outcompeting the effect of endogenous wild-type STXBP2. Interestingly, arginine 190 is located in a structurally conserved region of STXBP2 where other f-HLH-5 mutations have been identified. Collectively, data strongly suggest that STXBP2-R190C is a deleterious variant that may act in a dominant-negative manner by probably stabilizing non-productive interactions between STXBP2/STX11 complex and other still unknown factors such as the membrane surface or Munc13-4 protein and thus impairing the release of cytolytic granules. In addition to the contribution of STXBP2-R190C to f-HLH, the accompanied G6PD mutation may have compounded the clinical symptoms; however, the extent by which G6PD deficiency has contributed to HLH in our patient remains unclear.
登录
查看更多内容
DOI：
10.1073/pnas.1313474110
发表时间：
2013-11-19
影响因子：
11.1
作者：
Hackmann, Yvonne;Graham, Stephen C.;Griffiths, Gillian M.
通讯作者：
Griffiths, Gillian M.
影响因子：
16.2
作者：
Lai Y;Choi UB;Leitz J;Rhee HJ;Lee C;Altas B;Zhao M;Pfuetzner RA;Wang AL;Brose N;Rhee J;Brunger AT
通讯作者：
Brunger AT
影响因子：
20.3
作者：
Bryceson, Yenan T.;Pende, Daniela;Ehl, Stephan
通讯作者：
Ehl, Stephan
影响因子：
15.9
作者：
Cote, Marjorie;Menager, Mickael M.;de Saint Basile, Genevieve
通讯作者：
de Saint Basile, Genevieve
影响因子：
20.3
作者：
Al Hawas, Rania;Ren, Qiansheng;Whiteheart, Sidney W.
通讯作者：
Whiteheart, Sidney W.