Dissection of epistasis in oligogenic Bardet-Biedl syndrome
Dissection of epistasis in oligogenic Bardet-Biedl syndrome
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DOI：
10.1038/nature04370
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发表时间：
2006-01-19
期刊：
影响因子：
64.8
通讯作者：
Katsanis, N
中科院分区：
文献类型：
--
作者：
Badano, JL;Leitch, CC;Katsanis, N
上位性相互作用在表型变异中具有重要作用，但对此类现象的遗传解剖仍然具有挑战性（1）。在这里，我们报告了一个新的基因座MGC 1203的鉴定，该基因座为Bardet-Biedl综合征（BBS）（一种多效性寡基因性疾病）提供上位等位基因（2-9）。MGC 1203编码一种与BBS蛋白相互作用并共定位的中心粒周蛋白。两个独立的BBS队列的测序结果显示，患者中杂合C430 T突变显著富集，传递不平衡检验（TDT）显示该变体存在强烈的过度传递。进一步的分析表明，430 T等位基因增强了隐蔽剪接受体位点的使用，导致提前终止密码子（PTC）的引入和稳态MGC 1203信使RNA水平的降低。最后，在斑马鱼中的人类基因型的重演表明，适度抑制mgc 1203对BBS morphants的发育表型产生上位效应。我们的数据表明，如何结合使用生物化学，遗传和体内工具，可以促进上位现象的解剖，并提高我们的赞赏表型变异的遗传基础。
Epistatic interactions have an important role in phenotypic variability, yet the genetic dissection of such phenomena remains challenging(1). Here we report the identification of a novel locus, MGC1203, that contributes epistatic alleles to Bardet-Biedl syndrome (BBS), a pleiotropic, oligogenic disorder(2-9). MGC1203 encodes a pericentriolar protein that interacts and colocalizes with the BBS proteins. Sequencing of two independent BBS cohorts revealed a significant enrichment of a heterozygous C430T mutation in patients, and a transmission disequilibrium test (TDT) showed strong over-transmission of this variant. Further analyses showed that the 430T allele enhances the use of a cryptic splice acceptor site, causing the introduction of a premature termination codon (PTC) and the reduction of steady-state MGC1203 messenger RNA levels. Finally, recapitulation of the human genotypes in zebrafish shows that modest suppression of mgc1203 exerts an epistatic effect on the developmental phenotype of BBS morphants. Our data demonstrate how the combined use of biochemical, genetic and in vivo tools can facilitate the dissection of epistatic phenomena, and enhance our appreciation of the genetic basis of phenotypic variability.