NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation.
NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation.
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DOI：
10.1084/jem.20192275
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发表时间：
2020-12-07
期刊：
影响因子：
--
通讯作者：
Bahram S
中科院分区：
文献类型：
--
作者：
Castro CN;Rosenzwajg M;Carapito R;Shahrooei M;Konantz M;Khan A;Miao Z;Groß M;Tranchant T;Radosavljevic M;Paul N;Stemmelen T;Pitoiset F;Hirschler A;Nespola B;Molitor A;Rolli V;Pichot A;Faletti LE;Rinaldi B;Friant S;Mednikov M;Karauzum H;Aman MJ;Carapito C;Lengerke C;Ziaee V;Eyaid W;Ehl S;Alroqi F;Parvaneh N;Bahram S
NCKAP1L是肌动蛋白细胞骨架的调节因子，其双等位基因突变可导致免疫缺陷、淋巴细胞增殖和高炎症，并具有噬血细胞淋巴组织细胞增多症的特征。免疫突触形成受损，早期T细胞激活和前缘形成，中性粒细胞迁移缺陷是这种新型“放线病”的特征。nck相关蛋白1样（NCKAP1L）基因，也称为造血蛋白1 (hm -1)，编码肌动蛋白细胞骨架的造血谱系特异性调节因子。缺乏nckap1l的小鼠在淋巴细胞发育、吞噬和中性粒细胞迁移方面存在异常。在这里，我们首次报道了人类NCKAP1L缺陷病例。在两名中东血统的无血缘关系的患者中，NCKAP1L基因的隐性突变导致了免疫缺陷、淋巴细胞增殖和高炎症，表现为噬血细胞性淋巴组织细胞增多症。免疫表型分析显示CD4/CD8比例倒置，CD4+和CD8+细胞向记忆区主要转移，与RNA-seq/蛋白质组学联合分析一致，揭示了T细胞衰竭的特征。与NCKAP1L在肌动蛋白细胞骨架重组中的核心功能一致，患者的T细胞表现出早期活化、免疫突触形态和前缘形成受损。此外，斑马鱼中nckap1l的敲低导致中性粒细胞迁移缺陷。因此，NCKAP1L突变导致人类广泛的免疫失调，这可以归类为放线菌病。
Biallelic mutations in NCKAP1L, a regulator of the actin cytoskeleton, cause immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Impaired immune synapse formation, early T cell activation and leading edge formation, and defective neutrophil migration characterize this novel “actinopathy.” The Nck-associated protein 1–like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage–specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients’ T cells displayed impaired early activation, immune synapse morphology, and leading edge formation. Moreover, knockdown of nckap1l in zebrafish led to defects in neutrophil migration. Hence, NCKAP1L mutations lead to broad immune dysregulation in humans, which could be classified within actinopathies.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
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影响因子：
64.8
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DOI：
10.1056/nejmoa1413462
发表时间：
2015-06-18
期刊：
The New England journal of medicine
影响因子：
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Dobbs K;Domínguez Conde C;Zhang SY;Parolini S;Audry M;Chou J;Haapaniemi E;Keles S;Bilic I;Okada S;Massaad MJ;Rounioja S;Alwahadneh AM;Serwas NK;Capuder K;Çiftçi E;Felgentreff K;Ohsumi TK;Pedergnana V;Boisson B;Haskoloğlu Ş;Ensari A;Schuster M;Moretta A;Itan Y;Patrizi O;Rozenberg F;Lebon P;Saarela J;Knip M;Petrovski S;Goldstein DB;Parrott RE;Savas B;Schambach A;Tabellini G;Bock C;Chatila TA;Comeau AM;Geha RS;Abel L;Buckley RH;İkincioğulları A;Al-Herz W;Helminen M;Doğu F;Casanova JL;Boztuğ K;Notarangelo LD
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影响因子：
14.9
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影响因子：
20.3
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