DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes.
DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes.
复制标题
DOI：
10.1136/jmedgenet-2019-106805
复制
发表时间：
2021-07
影响因子：
4
通讯作者：
Khokha MK
中科院分区：
文献类型：
--
作者：
Marquez J;Mann N;Arana K;Deniz E;Ji W;Konstantino M;Mis EK;Deshpande C;Jeffries L;McGlynn J;Hugo H;Widmeier E;Konrad M;Tasic V;Morotti R;Baptista J;Ellard S;Lakhani SA;Hildebrandt F;Khokha MK
纤毛是动态的细胞延伸，产生和感知信号以协调适当的发育和组织稳态。它们依赖于细胞的潜在极化来参与信号传递。纤毛功能障碍是众所周知的几种疾病的病因，这些疾病会影响多个器官系统，包括肾脏、大脑、心脏、呼吸道、骨骼和视网膜。在来自四个不相关家族的个体中，我们发现了大5椎间盘（DLG5）的变异，其表现为多种病理。在我们的先证者中，我们也检查了患者的组织。我们在热带非洲爪蟾蛙胚胎中去除dlg5以产生一个功能丧失模型。最后，我们在青蛙模型中通过拯救实验检测了DLG5患者变异的致病性。发现DLG5变异的患者具有多种表型，包括囊性肾、肾病综合征、脑积水、肢体异常、先天性心脏病和颅面畸形。我们还观察到先证者囊肾组织中纤毛的缺失。在非洲爪蟾胚胎中敲低dlg5会重现许多这些表型，并导致多个组织中纤毛的缺失。与在缺乏DLG5的青蛙胚胎中引入野生型DLG5不同，在肾脏和大脑中引入DLG5患者变体在恢复适当的调解和组织形态方面基本上无效，这表明这些变体确实对功能有害。这些在患者组织和爪蟾中的发现揭示了DLG5突变如何导致疾病的组织特异性表现。DLG5对纤毛至关重要，许多患者的表型都在纤毛病谱中。
Cilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina. Among individuals from four unrelated families, we identified variants in discs large 5 (DLG5) that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model. Patients with variants of DLG5 were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function. These findings in both patient tissues and Xenopus shed light on how mutations in DLG5 may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.
登录
查看更多内容
影响因子：
10.5
作者：
Chong YC;Mann RK;Zhao C;Kato M;Beachy PA
通讯作者：
Beachy PA
影响因子：
7.2
作者：
Braun DA;Hildebrandt F
通讯作者：
Hildebrandt F
DOI：
10.1074/jbc.ra117.000847
发表时间：
2018-09-28
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Hoff S;Epting D;Falk N;Schroda S;Braun DA;Halbritter J;Hildebrandt F;Kramer-Zucker A;Bergmann C;Walz G;Lienkamp SS
通讯作者：
Lienkamp SS
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
13.6
作者：
Huber, Tobias B.;Hartleben, Bjoern;Schiffer, Mario
通讯作者：
Schiffer, Mario