Over-expression of DSCAM and COL6A2 cooperatively generates congenital heart defects.
Over-expression of DSCAM and COL6A2 cooperatively generates congenital heart defects.
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DOI：
10.1371/journal.pgen.1002344
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发表时间：
2011-11
期刊：
影响因子：
4.5
通讯作者：
Bier E
中科院分区：
文献类型：
--
作者：
Grossman TR;Gamliel A;Wessells RJ;Taghli-Lamallem O;Jepsen K;Ocorr K;Korenberg JR;Peterson KL;Rosenfeld MG;Bodmer R;Bier E
目前人类遗传学的一个重要挑战是鉴定介导复杂多基因疾病的相互作用的遗传基因座。唐氏综合征（Down syndrome，DS）是一种多基因遗传病，它是由21号染色体的部分或全部额外拷贝引起的。21号染色体远端附近的短间隔有助于先天性心脏病（CHD），各种间接遗传学证据表明，该区域的多个候选基因可能有助于这种表型。我们设计了一种分层遗传方法来识别相互作用的CHD候选基因。我们首先使用经过严格审查的果蝇心脏作为测定，通过单独表达和以所有可能的成对组合表达来鉴定相互作用的CHD候选基因，并测试对压力后节律性或心力衰竭的影响。这项综合分析确定DSCAM和COL6A2是相互作用最强的基因对。然后，我们在小鼠心脏中单独或组合过表达这两个基因。虽然单独的任一基因的过表达不影响存活力，并且对心脏生理学或形态学几乎没有影响，但是两种基因的共表达导致约50%的死亡率和严重的生理学和形态学缺陷，包括房间隔缺损和心脏肥大。在H9C2心脏细胞系中也观察到DSCAM和COL6A2之间的合作相互作用，并且这种相互作用的转录分析指向参与粘附和心脏肥大的基因。我们在定义DSCAM和COL6A2之间的合作相互作用的成功表明，我们已经采取的涉及人类作图数据，在果蝇中的综合组合筛选，并在小鼠和哺乳动物细胞系中的体内验证的多层次的遗传方法，应适用于确定特定的基因座介导的各种其他多基因疾病。大部分人类基因可能导致多基因疾病，但目前很少有实验方法来识别这些基因。例如，关于唐氏综合征患者中由21号染色体上的基因的额外拷贝引起的先天性心脏缺陷（CHD），尚不知道哪些基因促成了这种复杂的表型。在本文中，我们确定了两个基因，DSCAM和COL6A2强烈相互作用，以产生CHD时，在小鼠心脏适度的水平过度表达。这两个基因被鉴定为在果蝇心脏中过表达时相互作用最强的CHD候选基因对，在那里它们破坏了心脏功能的几个指标。然后，我们在小鼠心脏中单独或组合过表达这些基因，发现单独表达任何一个基因几乎没有影响，而在苍蝇中共同表达基因，导致心脏生理学和形态学的严重合作缺陷。我们在这项研究中遵循的策略广泛适用于识别与其他多基因疾病有关的基因，如肥胖症，自闭症和精神分裂症，这些疾病与多个基因的拷贝数改变有关。
A significant current challenge in human genetics is the identification of interacting genetic loci mediating complex polygenic disorders. One of the best characterized polygenic diseases is Down syndrome (DS), which results from an extra copy of part or all of chromosome 21. A short interval near the distal tip of chromosome 21 contributes to congenital heart defects (CHD), and a variety of indirect genetic evidence suggests that multiple candidate genes in this region may contribute to this phenotype. We devised a tiered genetic approach to identify interacting CHD candidate genes. We first used the well vetted Drosophila heart as an assay to identify interacting CHD candidate genes by expressing them alone and in all possible pairwise combinations and testing for effects on rhythmicity or heart failure following stress. This comprehensive analysis identified DSCAM and COL6A2 as the most strongly interacting pair of genes. We then over-expressed these two genes alone or in combination in the mouse heart. While over-expression of either gene alone did not affect viability and had little or no effect on heart physiology or morphology, co-expression of the two genes resulted in ≈50% mortality and severe physiological and morphological defects, including atrial septal defects and cardiac hypertrophy. Cooperative interactions between DSCAM and COL6A2 were also observed in the H9C2 cardiac cell line and transcriptional analysis of this interaction points to genes involved in adhesion and cardiac hypertrophy. Our success in defining a cooperative interaction between DSCAM and COL6A2 suggests that the multi-tiered genetic approach we have taken involving human mapping data, comprehensive combinatorial screening in Drosophila, and validation in vivo in mice and in mammalian cells lines should be applicable to identifying specific loci mediating a broad variety of other polygenic disorders. A large fraction of human genes may contribute to polygenic disorders, yet few experimental methods for identifying such genes are currently available. For example, with regard to congenital heart defects (CHD) caused by extra copies of genes on chromosome 21 in Down syndrome patients, it is not known which genes contribute to this complex phenotype. In this paper, we identify two genes, DSCAM and COL6A2 that interact strongly to produce CHD when over-expressed at modest levels in the mouse heart. These two genes were identified as the most strongly interacting pair of CHD candidate genes when over-expressed in the Drosophila heart, where they disrupted several indices of heart function. We then over-expressed these genes in the mouse heart alone or in combination and found that while expression of either gene alone had little or no effect, co-expression of the genes, as in flies, lead to severe cooperative defects in heart physiology and morphology. The strategy we have followed in this study is broadly applicable to identifying genes involved in other polygenic disorders, such as obesity, autism, and schizophrenia, which have been linked to altered copy number of multiple genes.
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影响因子：
4.4
作者：
Lockstone, H. E.;Harris, L. W.;Bahn, S.
通讯作者：
Bahn, S.
影响因子：
5.3
作者：
Sandri, C;Di Lisi, R;Schiaffino, S
通讯作者：
Schiaffino, S
DOI：
10.1073/pnas.0609278104
发表时间：
2007-03-06
影响因子：
11.1
作者：
Ocorr, Karen;Reeves, Nick L.;Bodmer, Rolf
通讯作者：
Bodmer, Rolf
影响因子：
10.8
作者：
Dunlevy, Louisa;Bennett, Mike;Mohun, Timothy
通讯作者：
Mohun, Timothy
心脏成纤维细胞通过Beta1整合素信号传导调节心肌增殖。
影响因子：
11.8
作者：
Leda, Masaki;Tsuchihashi, Takatoshi;Ivey, Kathryn N.;Ross, Robert S.;Hong, Ting-Ting;Shaw, Robin M.;Srivastava, Deepak
通讯作者：
Srivastava, Deepak