hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia.
hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia.
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DOI：
10.1084/jem.20180528
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发表时间：
2018-09-03
期刊：
影响因子：
--
通讯作者：
Caron KM
中科院分区：
文献类型：
--
作者：
Mackie DI;Al Mutairi F;Davis RB;Kechele DO;Nielsen NR;Snyder JC;Caron MG;Kliman HJ;Berg JS;Simms J;Poyner DR;Caron KM
使用遗传学，药理学和动物模型的方法，我们阐明了一种新的人类突变的G蛋白偶联受体，损害受体寡聚化和贩运，导致致命的，非免疫性水肿胎儿与逮捕淋巴发育。我们报告了第一例非免疫性胎儿水肿（NIHF）与G蛋白偶联受体降钙素受体样受体（hCALCRL）中V205的隐性、框内缺失相关。纯合性导致胎儿水肿死亡，而女性杂合性与自然流产和生育力低下有关。使用分子动力学建模和体外生化测定，我们表明，histopathy（V205 del）突变体的第一个细胞外环的错误折叠的结果，减少与其必需的受体伴侣，受体活性修饰蛋白（RAMP），易位到质膜和信号。使用三个独立的遗传小鼠模型，我们建立了肾上腺髓质素-β-RAMP 2轴是必要的和足够的驱动淋巴管增殖。淋巴管内皮细胞Calcrl或非内皮细胞Ramp 2的基因消融导致严重的NIHF，伴随胚胎死亡和胎盘病理学，与在人类中观察到的相似。我们的研究结果突出了一个新的候选基因，为人类先天性NIHF，并提供结构功能的见解，这一信号轴为人类生理学。
Using genetic, pharmacological and animal model approaches, we elucidate a novel human mutation in a G protein coupled receptor that impairs receptor oligomerization and trafficking leading to fatal, non-immune hydrops fetalis associated with arrested lymphatic development. We report the first case of nonimmune hydrops fetalis (NIHF) associated with a recessive, in-frame deletion of V205 in the G protein–coupled receptor, Calcitonin Receptor-Like Receptor (hCALCRL). Homozygosity results in fetal demise from hydrops fetalis, while heterozygosity in females is associated with spontaneous miscarriage and subfertility. Using molecular dynamic modeling and in vitro biochemical assays, we show that the hCLR(V205del) mutant results in misfolding of the first extracellular loop, reducing association with its requisite receptor chaperone, receptor activity modifying protein (RAMP), translocation to the plasma membrane and signaling. Using three independent genetic mouse models we establish that the adrenomedullin–CLR–RAMP2 axis is both necessary and sufficient for driving lymphatic vascular proliferation. Genetic ablation of either lymphatic endothelial Calcrl or nonendothelial Ramp2 leads to severe NIHF with embryonic demise and placental pathologies, similar to that observed in humans. Our results highlight a novel candidate gene for human congenital NIHF and provide structure–function insights of this signaling axis for human physiology.
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影响因子：
2.9
作者：
Benkert, Pascal;Tosatto, Silvio C. E.;Schwede, Torsten
通讯作者：
Schwede, Torsten
影响因子：
5.3
作者：
Alders, Marielle;Al-Gazali, Lihadh;Hennekam, Raoul C.
通讯作者：
Hennekam, Raoul C.
影响因子：
2
作者：
Bellini, Carlo;Donarini, Gloria;Hennekam, Raoul C.
通讯作者：
Hennekam, Raoul C.
DOI：
10.1093/bioinformatics/btq662
发表时间：
2011-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Benkert P;Biasini M;Schwede T
通讯作者：
Schwede T
影响因子：
3.9
作者：
Barwell, James;Woolley, Michael J.;Poyner, David R.
通讯作者：
Poyner, David R.