Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome.
Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome.
复制标题
作为单基因肾病综合征候选者的SYNPO2隐性突变。
DOI：
10.1016/j.ekir.2020.10.040
复制
发表时间：
2021-03
影响因子：
6
通讯作者：
Hildebrandt F
中科院分区：
文献类型：
--
作者：
Mao Y;Schneider R;van der Ven PFM;Assent M;Lohanadan K;Klämbt V;Buerger F;Kitzler TM;Deutsch K;Nakayama M;Majmundar AJ;Mann N;Hermle T;Onuchic-Whitford AC;Zhou W;Margam NN;Duncan R;Marquez J;Khokha M;Fathy HM;Kari JA;El Desoky S;Eid LA;Awad HS;Al-Saffar M;Mane S;Lifton RP;Fürst DO;Shril S;Hildebrandt F
大约60个基因中的大多数如果突变会导致类固醇耐药肾病综合征（SRNS），在肾小球足细胞中高度表达，使SRNS成为“足细胞病”。我们对1200例肾病综合征（NS）患者进行了全外显子组测序（WES）。我们在2例儿童期发病的NS患者中发现了SYNPO 2（synaptopodin-2）的纯合截断和纯合错义突变（p.Lys1124Thr和p.Ala1134Thr）。我们发现SYNPO 2在足细胞和系膜细胞中表达;然而，值得注意的是，成人和大鼠肾脏冷冻切片的免疫荧光染色表明SYNPO 2主要定位于系膜细胞。亚细胞定位研究表明，在这些细胞中，SYNPO 2与α-辅肌动蛋白和含有细丝蛋白A−的F-肌动蛋白细丝部分共定位。在系膜细胞或足细胞中转染后，EGFP-SYNPO 2与α-辅肌动蛋白-4共定位，该基因在人类常染色体显性SRNS中突变。SYNPO 2过表达增加系膜细胞迁移率（MMR），而shRNA敲低降低MMR。通过转染野生型小鼠Synpo 2 cDNA挽救了MMR降低，但仅部分通过代表NS患者突变的cDNA。阿普复合物抑制剂CK 666可抑制SYNPO 2过表达引起的系膜细胞迁移率（MMR）增加。在足细胞中SYNPO 2 shRNA敲低降低了活性Rac 1，这是通过转染野生型SYNPO 2 cDNA而不是通过代表任何2种突变变体的cDNA来拯救的。我们发现，SYNPO 2变异可能导致Rac 1-ARP 3失调，并可能在肾病综合征的发病机制中发挥作用。
Most of the approximately 60 genes that if mutated cause steroid-resistant nephrotic syndrome (SRNS) are highly expressed in the glomerular podocyte, rendering SRNS a “podocytopathy.” We performed whole-exome sequencing (WES) in 1200 nephrotic syndrome (NS) patients. We discovered homozygous truncating and homozygous missense mutation in SYNPO2 (synaptopodin-2) (p.Lys1124∗ and p.Ala1134Thr) in 2 patients with childhood-onset NS. We found SYNPO2 expression in both podocytes and mesangial cells; however, notably, immunofluorescence staining of adult human and rat kidney cryosections indicated that SYNPO2 is localized mainly in mesangial cells. Subcellular localization studies reveal that in these cells SYNPO2 partially co-localizes with α-actinin and filamin A−containing F-actin filaments. Upon transfection in mesangial cells or podocytes, EGFP-SYNPO2 co-localized with α-actinin-4, which gene is mutated in autosomal dominant SRNS in humans. SYNPO2 overexpression increases mesangial cell migration rate (MMR), whereas shRNA knockdown reduces MMR. Decreased MMR was rescued by transfection of wild-type mouse Synpo2 cDNA but only partially by cDNA representing mutations from the NS patients. The increased mesangial cell migration rate (MMR) by SYNPO2 overexpression was inhibited by ARP complex inhibitor CK666. SYNPO2 shRNA knockdown in podocytes decreased active Rac1, which was rescued by transfection of wild-type SYNPO2 cDNA but not by cDNA representing any of the 2 mutant variants. We show that SYNPO2 variants may lead to Rac1-ARP3 dysregulation, and may play a role in the pathogenesis of nephrotic syndrome.
登录
查看更多内容
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：
6
作者：
Lin, F;Yu, YP;Luo, JH
通讯作者：
Luo, JH
影响因子：
9.8
作者：
Gee, Heon Yung;Ashraf, Shazia;Hildebrandt, Friedhelm
通讯作者：
Hildebrandt, Friedhelm
足细胞GTP酶调节肾脏过滤器动力学。
影响因子：
19.6
作者：
通讯作者：
--
影响因子：
--
作者：
Kai F;Fawcett JP;Duncan R
通讯作者：
Duncan R