Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model.
Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model.
复制标题
DOI：
10.1007/s00467-022-05440-5
复制
发表时间：
2022-11
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
编码核孔复合物（NPC）蛋白的基因变异是一种新发现的导致儿童激素耐药型肾病综合征（SRNS）的原因。最近描述NUP 93变体的报告表明，这些变体可能是儿童发病SRNS的重要原因。我们报告NUP 93的情况下，在英国和证明在体内功能的影响，NUP 93消耗在苍蝇（果蝇）肾细胞模型。对来自患有肾病综合征（Nephros）的患者的国家队列的337名儿科SRNS患者进行全外显子组和/或全基因组测序。对患者进行了70多个已知与肾病综合征（NS）相关的基因的筛查。D.通过使用肾细胞限制性驱动子的RNA干扰实现黑腹果蝇Nup 93敲低。在3例散发性和2例家族性儿童SRNS中检测到6种新型纯合和复合杂合NUP 93变体，其组织学特征为局灶节段性肾小球硬化（FSGS），并在临床诊断后12个月内进展为肾衰竭。在D.在成体心包肾细胞中，Nup 93 -1和Nup 93 -2导致高达82%的显著信号降低，伴随着NPC蛋白表达的破坏。此外，存活至成年的Nup 93 -1和Nup 93 -2沉默果蝇的肾细胞形态高度异常。我们扩大了NUP 93变异在儿科发病SRNS中检测到的谱，并证明了其在全国队列中的发病率。D.黑腹果蝇Nup 93直系同源物引起严重的肾细胞表型，表明核孔蛋白复合物在足细胞生物学中的重要作用。图形摘要的更高分辨率版本可作为补充信息在线版本包含补充材料，可在10.1007/s 00467 -022-05440-5获得。
Variants in genes encoding nuclear pore complex (NPC) proteins are a newly identified cause of paediatric steroid-resistant nephrotic syndrome (SRNS). Recent reports describing NUP93 variants suggest these could be a significant cause of paediatric onset SRNS. We report NUP93 cases in the UK and demonstrate in vivo functional effects of Nup93 depletion in a fly (Drosophila melanogaster) nephrocyte model. Three hundred thirty-seven paediatric SRNS patients from the National cohort of patients with Nephrotic Syndrome (NephroS) were whole exome and/or whole genome sequenced. Patients were screened for over 70 genes known to be associated with Nephrotic Syndrome (NS). D. melanogaster Nup93 knockdown was achieved by RNA interference using nephrocyte-restricted drivers. Six novel homozygous and compound heterozygous NUP93 variants were detected in 3 sporadic and 2 familial paediatric onset SRNS characterised histologically by focal segmental glomerulosclerosis (FSGS) and progressing to kidney failure by 12 months from clinical diagnosis. Silencing of the two orthologs of human NUP93 expressed in D. melanogaster, Nup93-1, and Nup93-2 resulted in significant signal reduction of up to 82% in adult pericardial nephrocytes with concomitant disruption of NPC protein expression. Additionally, nephrocyte morphology was highly abnormal in Nup93-1 and Nup93-2 silenced flies surviving to adulthood. We expand the spectrum of NUP93 variants detected in paediatric onset SRNS and demonstrate its incidence within a national cohort. Silencing of either D. melanogaster Nup93 ortholog caused a severe nephrocyte phenotype, signaling an important role for the nucleoporin complex in podocyte biology. A higher resolution version of the Graphical abstract is available as Supplementary information The online version contains supplementary material available at 10.1007/s00467-022-05440-5.
登录
查看更多内容
影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
3
作者：
Bezdicka, Martin;Stolbova, Sarka;Zieg, Jakub
通讯作者：
Zieg, Jakub
影响因子：
15.9
作者：
Gee, Heon Yung;Zhang, Fujian;Hildebrandt, Friedhelm
通讯作者：
Hildebrandt, Friedhelm
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G