The RetC620R mutation affects renal and enteric development in a mouse model of Hirschsprung's disease
The RetC620R mutation affects renal and enteric development in a mouse model of Hirschsprung's disease
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DOI：
10.2353/ajpath.2006.050607
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发表时间：
2006-04-01
影响因子：
6
通讯作者：
Bongarzone, I
中科院分区：
文献类型：
--
作者：
Carniti, C;Belluco, S;Bongarzone, I
在罕见的家族中，位于外显子10（特别是在位置609、618和620）的RET酪氨酸激酶受体取代可伴随引起MEN 2A（多发性内分泌瘤2A型）或FMTC（家族性甲状腺髓样癌）癌症综合征和先天性巨结肠症（HSCR）。没有动物模型模拟MEN 2病理学和HSCR的共存是可用的，这些激活突变与发育缺陷的关联仍然是一个未解决的问题。这项工作的目的是研究RETC 620 R取代在功能获得和功能丧失RET相关疾病发病机制中的意义。我们报告一代罚款的小鼠携带C620R突变的Ret基因。尽管Ret（C620R）纯合子在肾器官发生和肠神经系统发育方面显示严重缺陷，导致围产期死亡。Ret（C620R）杂合子概括了HSCR的特征，包括胃肠道神经节细胞减少症。令人惊讶的是，杂合子并没有表现出任何缺陷，在甲状腺可能是由于获得性功能突变。Ret（C620R）等位基因负责HSCR并影响肾脏和肠神经系统（ENS）的发育。这些小鼠代表了用于研究治疗HSCR疾病的新治疗方法的有趣模型。
In rare families RET tyrosine kinase receptor substitutions located in exon 10 (especially at positions 609, 618, and 620) can concomitantly cause the MEN 2A (multiple endocrine neoplasia type 2A) or FMTC (familial medullary thyroid carcinoma) cancer syndromes, and Hirschsprung's disease (HSCR). No animal model mimicking the co-existence of the MEN 2 pathology and HSCR is available, and the association of these activating mutations with a developmental defect still represents an unresolved problem. The aim of this work was to investigate the significance of the RETC620R substitution in the pathogenesis of both gain- and loss-of-function RET-associated diseases. We report the generation of a fine of mice carrying the C620R mutation in the Ret gene. Although Ret(C620R) homozygotes display severe defects in kidney organogenesis and enteric nervous system development leading to perinatal lethality. Ret(C620R) heterozygotes recapitulate features characteristic of HSCR including hypoganglionosis of the gastrointestinal tract. Surprisingly, heterozygotes do not show any defects in the thyroid that might be attributable to a gain-of-function mutation. The Ret(C620R) allele is responsible for HSCR and affects the development of kidneys and the enteric nervous system (ENS). These mice represent an interesting model for studying new therapeutic approaches for the treatment of HSCR disease.