A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition.
A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition.
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Costello 综合征小鼠模型揭示了 Ang II 介导的高血压病症。
DOI：
10.1172/jci34385
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Barbacid,Mariano
中科院分区：
文献类型：
--
作者：
Schuhmacher,AlbertoJ;Guerra,Carmen;Sauzeau,Vincent;Canamero,Marta;Bustelo,XoseR;Barbacid,Mariano
H-RA Soncogenes的种系激活是Costello综合征（CS）的主要原因，Costello综合征是一种神经-心脏-面部-皮肤发育综合征。在这里，我们描述了一代的小鼠模型CS通过引入一个致癌的Gly 12 Val突变的小鼠H-Ras基因座使用同源重组在ES细胞。内源性H-RasG 12 V癌基因的种系表达，即使在纯合子，导致乳腺增生。然而，这些小鼠中的肿瘤发展是罕见的。H-RasG 12 V突变小鼠与CS患者中观察到的一些异常密切表型相似，包括面部畸形和心肌病。这些小鼠还表现出心血管系统稳态的改变，包括全身性高血压的发展、广泛的血管重塑以及心脏和肾脏的纤维化。这种表型是年龄依赖性的，并且是肾素-血管紧张素II系统异常上调的结果。用血管紧张素II生物合成抑制剂巯甲丙脯酸治疗，防止了高血压疾病、血管重塑以及心脏和肾脏纤维化的发展。此外，它部分缓解了观察到的心肌病。这些小鼠应该有助于阐明CS症状的病因，识别其他缺陷，并评估潜在的治疗策略。
Germline activation of H-RASoncogenes is the primary cause of Costello syndrome (CS), a neuro-cardio-facio-cutaneous developmental syndrome. Here we describe the generation of a mouse model of CS by introduction of an oncogenic Gly12Val mutation in the mouse H-Raslocus using homologous recombination in ES cells. Germline expression of the endogenous H-RasG12Voncogene, even in homozygosis, resulted in hyperplasia of the mammary gland. However, development of tumors in these mice was rare. H-RasG12Vmutant mice closely phenocopied some of the abnormalities observed in patients with CS, including facial dysmorphia and cardiomyopathies. These mice also displayed alterations in the homeostasis of the cardiovascular system, including development of systemic hypertension, extensive vascular remodeling, and fibrosis in both the heart and the kidneys. This phenotype was age dependent and was a consequence of the abnormal upregulation of the renin–Ang II system. Treatment with captopril, an inhibitor of Ang II biosynthesis, prevented development of the hypertension condition, vascular remodeling, and heart and kidney fibrosis. In addition, it partially alleviated the observed cardiomyopathies. These mice should help in elucidating the etiology of CS symptoms, identifying additional defects, and evaluating potential therapeutic strategies.
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SOS1 是第二常见的 Noonan 基因，但在心脏-面部-皮肤综合征中不起主要作用
影响因子：
4
作者：
M. Zenker;D. Horn;D. Wieczorek;J. Allanson;S. Pauli;I. van der Burgt;H. Doerr;H. Gaspar;M. Hofbeck;G. Gillessen‐Kaesbach;A. Koch;P. Meinecke;S. Mundlos;Anja Nowka;A. Rauch;Silke Reif;C. von Schnakenburg;H. Seidel;L. Wehner;C. Zweier;Susanne Bauhuber;Verena Matejas;C. Kratz;Christoph Thomas;K. Kutsche
通讯作者：
K. Kutsche
影响因子：
4.8
作者：
Jerkic, M;Rivas-Elena, JV;López-Novoa, IM
通讯作者：
López-Novoa, IM
影响因子：
2.7
作者：
Thomson, JM;Parrott, WA
通讯作者：
Parrott, WA
影响因子：
82.9
作者：
Araki, T;Mohi, MG;Neel, BG
通讯作者：
Neel, BG
DOI：
10.1073/pnas.90.18.8424
发表时间：
1993-09-15
影响因子：
11.1
作者：
NAGY, A;ROSSANT, J;RODER, JC
通讯作者：
RODER, JC