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本文引用的文献

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Exome Sequencing and Identification of Phenocopies in Patients With Clinically Presumed Hereditary Nephropathies.外显子组测序与临床疑似遗传性肾病患者表型模拟的鉴定。
Am J Kidney Dis. 2020 Oct;76(4):460-470. doi: 10.1053/j.ajkd.2019.12.008. Epub 2020 Apr 28.
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FSGS-Causing INF2 Mutation Impairs Cleaved INF2 N-Fragment Functions in Podocytes.导致 FSGS 的 INF2 突变会损害足细胞中裂解的 INF2 N 片段的功能。
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Regulation of INF2-mediated actin polymerization through site-specific lysine acetylation of actin itself.通过肌动蛋白自身赖氨酸特异性乙酰化调节 INF2 介导的肌动蛋白聚合。
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Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome.全外显子测序在激素抵抗型肾病综合征中的反向表型研究。
Clin J Am Soc Nephrol. 2020 Jan 7;15(1):89-100. doi: 10.2215/CJN.06060519. Epub 2019 Dec 12.
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Fibronectin is up-regulated in podocytes by mechanical stress.纤连蛋白在机械应力的作用下在上皮细胞中上调。
FASEB J. 2019 Dec;33(12):14450-14460. doi: 10.1096/fj.201900978RR. Epub 2019 Nov 1.
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Disruption of MAGI2-RapGEF2-Rap1 signaling contributes to podocyte dysfunction in congenital nephrotic syndrome caused by mutations in MAGI2.MAGI2-RapGEF2-Rap1 信号通路的破坏导致 MAGI2 突变引起的先天性肾病综合征中足细胞功能障碍。
Kidney Int. 2019 Sep;96(3):642-655. doi: 10.1016/j.kint.2019.03.016. Epub 2019 Mar 28.
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Genetic compensation triggered by mutant mRNA degradation.突变 mRNA 降解引发的遗传补偿。
Nature. 2019 Apr;568(7751):193-197. doi: 10.1038/s41586-019-1064-z. Epub 2019 Apr 3.
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ARP3 Controls the Podocyte Architecture at the Kidney Filtration Barrier.ARP3 控制肾脏过滤屏障处的足细胞结构。
Dev Cell. 2018 Dec 17;47(6):741-757.e8. doi: 10.1016/j.devcel.2018.11.011. Epub 2018 Nov 29.
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Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease.肾单位特异性遗传变异分析鉴定慢性肾脏病新途径。
Nat Med. 2018 Nov;24(11):1721-1731. doi: 10.1038/s41591-018-0194-4. Epub 2018 Oct 1.
10
A Single-Cell Transcriptome Atlas of the Mouse Glomerulus.小鼠肾小球单细胞转录组图谱。
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DAAM2 变异导致肌动蛋白调控异常型肾病综合征。

DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation.

机构信息

Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Department of Biology, Brandeis University, Waltham, MA 02454, USA.

出版信息

Am J Hum Genet. 2020 Dec 3;107(6):1113-1128. doi: 10.1016/j.ajhg.2020.11.008. Epub 2020 Nov 23.

DOI:10.1016/j.ajhg.2020.11.008
PMID:
33232676
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7820625/
Abstract

The discovery of >60 monogenic causes of nephrotic syndrome (NS) has revealed a central role for the actin regulators RhoA/Rac1/Cdc42 and their effectors, including the formin INF2. By whole-exome sequencing (WES), we here discovered bi-allelic variants in the formin DAAM2 in four unrelated families with steroid-resistant NS. We show that DAAM2 localizes to the cytoplasm in podocytes and in kidney sections. Further, the variants impair DAAM2-dependent actin remodeling processes: wild-type DAAM2 cDNA, but not cDNA representing missense variants found in individuals with NS, rescued reduced podocyte migration rate (PMR) and restored reduced filopodia formation in shRNA-induced DAAM2-knockdown podocytes. Filopodia restoration was also induced by the formin-activating molecule IMM-01. DAAM2 also co-localizes and co-immunoprecipitates with INF2, which is intriguing since variants in both formins cause NS. Using in vitro bulk and TIRF microscopy assays, we find that DAAM2 variants alter actin assembly activities of the formin. In a Xenopus daam2-CRISPR knockout model, we demonstrate actin dysregulation in vivo and glomerular maldevelopment that is rescued by WT-DAAM2 mRNA. We conclude that DAAM2 variants are a likely cause of monogenic human SRNS due to actin dysregulation in podocytes. Further, we provide evidence that DAAM2-associated SRNS may be amenable to treatment using actin regulating compounds.

摘要

超过 60 种单基因肾病综合征 (NS) 的病因已被发现,这揭示了肌动蛋白调节因子 RhoA/Rac1/Cdc42 及其效应物(包括formin INF2)的核心作用。通过全外显子组测序 (WES),我们在四个不相关的类固醇耐药性 NS 家族中发现了formin DAAM2 的双等位基因变异。我们表明 DAAM2 在足细胞和肾切片中定位于细胞质。此外,这些变体损害了 DAAM2 依赖性的肌动蛋白重塑过程:野生型 DAAM2 cDNA,但不是在患有 NS 的个体中发现的错义变体 cDNA,挽救了降低的足细胞迁移率 (PMR),并恢复了 shRNA 诱导的 DAAM2 敲低足细胞中减少的丝状伪足形成。formin 激活分子 IMM-01 也诱导丝状伪足的恢复。DAAM2 还与 INF2 共定位和共免疫沉淀,这很有趣,因为两种formin 的变体都会导致 NS。使用体外批量和 TIRF 显微镜检测,我们发现 DAAM2 变体改变了formin 的肌动蛋白组装活性。在 Xenopus daam2-CRISPR 敲除模型中,我们证明了体内肌动蛋白失调和肾小球发育不良,而 WT-DAAM2 mRNA 可挽救这种情况。我们得出结论,由于足细胞中的肌动蛋白失调,DAAM2 变体可能是人类单基因 SRNS 的一个原因。此外,我们提供的证据表明,DAAM2 相关的 SRNS 可能可以通过使用肌动蛋白调节化合物进行治疗。