Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects
Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects
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DOI：
10.1038/81695
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发表时间：
2000-11-01
期刊：
影响因子：
30.8
通讯作者：
Casey, B
中科院分区：
文献类型：
--
作者：
Bamford, RN;Roessler, E;Casey, B
所有脊椎动物的内脏器官都具有不对称的特征，心尖、胃和脾位于左侧，肝脏和胆囊位于右侧（1-3）。左右（L-R）轴异常或偏侧性缺陷在人类中很常见（1/8，500活产）。几种基因（如Nodal、Ebaf和Pitx 2）与模式生物体中的L-R器官定位有关（2-4）。在人类中，相对较少的基因与小百分比的人类部位缺陷相关。这些包括ZIC 3（参考文献5）、LEFTB（以前为LEFTY 2;参考文献6）和ACVR 2B（编码激活素受体IIB;参考文献7）。EGF-CFC基因（8）、小鼠Cfc 1（编码隐藏蛋白;参考文献9）和斑马鱼独眼针头（oep;参考文献10，11）对于L-R轴的建立是必不可少的（12，13）。EGF-CFC蛋白作为Nodal相关信号的辅因子（11），其也涉及L-R轴发育（4）。在这里，我们确定了在人类CFC 1（编码CFPPTIC蛋白）的功能缺失突变与异位表型（随机器官定位）的患者。突变蛋白在转染细胞中具有异常的细胞定位，并且在斑马鱼突变体拯救测定中具有功能缺陷。我们的研究结果表明，EGF-CFC基因和Nodal信号在左右轴形成中的重要作用从鱼类到人类都是保守的。此外，我们的研究结果支持环境和/或遗传修饰剂在确定人类最终表型中的作用。
Ail vertebrates display a characteristic asymmetry of internal organs with the cardiac apex, stomach and spleen towards the left, and the liver and gall bladder on the right(1-3). Left-right (L-R) axis abnormalities or laterality defects are common in humans (1 in 8,500 live births). Several genes (such as Nodal, Ebaf and Pitx2) have been implicated in L-R organ positioning in model organisms(2-4), In humans, relatively few genes have been associated with a small percentage of human situs defects. These include ZIC3 (ref. 5), LEFTB (formerly LEFTY2; ref. 6) and ACVR2B (encoding activin receptor IIB; ref, 7). The EGF-CFC genes(8), mouse Cfc1 (encoding the Cryptic protein; ref. 9) and zebrafish one-eyed pinhead (oep; refs 10,11) are essential for the establishment of the L-R axis(12,13). EGF-CFC proteins act as co-factors for Nodal-related signals(11), which have also been implicated in L-R axis development(4). Here we identify loss-of-function mutations in human CFC1 (encoding the CRYPTIC protein) in patients with heterotaxic phenotypes (randomized organ positioning). The mutant proteins have aberrant cellular localization in transfected cells and are functionally defective in a zebrafish oepmutant rescue assay. Our findings indicate that the essential role of EGF-CFC genes and Nodal signalling in left-right axis formation is conserved from fish to humans. Moreover, our results support a role for environmental and/or genetic modifiers in determining the ultimate phenotype in humans.