Generation of mice lacking DUF1220 protein domains: effects on fecundity and hyperactivity.
Generation of mice lacking DUF1220 protein domains: effects on fecundity and hyperactivity.
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DOI：
10.1007/s00335-014-9545-8
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发表时间：
2015-02
期刊：
影响因子：
2.5
通讯作者：
Sikela, J. M.
中科院分区：
文献类型：
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作者：
Keeney, J. G.;O'Bleness, M. S.;Anderson, N.;Davis, J. M.;Arevalo, N.;Busquet, N.;Chick, W.;Rozman, J.;Hoelter, S. M.;Garrett, L.;Horsch, M.;Beckers, J.;Wurst, W.;Klingenspor, M.;Restrepo, D.;de Angelis, M. Hrabe;Sikela, J. M.
编码DUF1220蛋白结构域的序列显示出基因组中任何编码区域中最极端的人类谱系特异性拷贝数增加，并且与人类大脑进化有关。此外，DUF1220拷贝数（剂量）在正常人群和与脑大小病变（1q21相关的小头畸形和大头畸形）相关的个体中都与影响人类的脑大小有关。最近，DUF1220亚型的剂量增加与自闭症初级症状的严重程度增加有关。尽管存在这些有趣的关联，但这些结构域的功能尚未被描述。作为解决这个问题的第一步，我们通过去除小鼠基因组中编码的单个DUF1220结构域（祖先形式），开发了DUF1220功能的第一个转基因模型。在假设生成练习中，这些小鼠通过197种不同的表型测量进行评估。虽然DUF1220-minus （KO）小鼠没有明显的解剖特征，但它们的繁殖力明显降低（χ2= 19.1, df = 2, p = 7.0 × 10−5）。进一步广泛的表型分析表明，DUF1220小鼠的多动症（p < 0.05）和大脑基因表达水平的变化与不同的神经功能和疾病相关。其他符合统计学意义的变化包括男性突变体血浆葡萄糖浓度升高（通过曲线下面积，AUC 0-30和AUC 30-120测量），男性突变体空腹葡萄糖水平，钠水平降低，男性肝功能指标ALAT/GPT水平升高，碱性磷酸酶（也是肝功能指标）水平，心电图平均R和SR幅度，IgG3水平升高，CD4:CD8细胞比值降低，T细胞频率降低；虽然应该指出的是，这些差异中有许多是相当小的，需要进一步的研究。DUF1220缺失与过度活跃表型的联系与DUF1220过表达导致线粒体功能下调的单独研究结果一致，并可能提示在发育代谢中起作用。最后，我们观察到与KO小鼠相关的繁殖力大幅下降，这表明祖先的DUF1220结构域提供了重要的生物学功能，对生存能力和繁殖成功至关重要。
Sequences encoding DUF1220 protein domains show the most extreme human lineage-specific copy number increase of any coding region in the genome and have been linked to human brain evolution. In addition, DUF1220 copy number (dosage) has been implicated in influencing brain size within the human species, both in normal populations and in individuals associated with brain size pathologies (1q21-associated microcephaly and macrocephaly). More recently, increasing dosage of a subtype of DUF1220 has been linked with increasing severity of the primary symptoms of autism. Despite these intriguing associations, a function for these domains has not been described. As a first step in addressing this question we have developed the first transgenic model of DUF1220 function by removing the single DUF1220 domain (the ancestral form) encoded in the mouse genome. In a hypothesis generating exercise, these mice were evaluated by 197 different phenotype measurements. While resulting DUF1220-minus (KO) mice show no obvious anatomical peculiarities, they exhibit a significantly reduced fecundity (χ2= 19.1, df = 2, p = 7.0 × 10−5). Further extensive phenotypic analyses suggest hyperactivity (p < 0.05) of DUF1220 mice and changes in gene expression levels of brain associated with distinct neurological functions and disease. Other changes that met statistical significance include an increase in plasma glucose concentration (as measured by Area Under the Curve, AUC 0-30 and AUC 30-120) in male mutants, fasting glucose levels, reduce sodium levels in male mutants, increased levels of the liver functional indicator ALAT/GPT in males, levels of alkaline phosphatase (also an indicator of liver function), mean R and SR amplitude by electrocardiography, elevated IgG3 levels, a reduced ratio of CD4:CD8 cells, and a reduced frequency of T cells; though it should be noted that many of these differences are quite small and require further examination. The linking of DUF1220 loss to a hyperactive phenotype is consistent with separate findings in which DUF1220 over expression results in a down-regulation of mitochondrial function, and potentially suggest a role in developmental metabolism. Finally, the substantially reduced fecundity we observe associated with KO mice argues that the ancestral DUF1220 domain provides an important biological function that is critical to survivability and reproductive success.
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影响因子：
--
作者：
Uys GM;Ramburan A;Loos B;Kinnear CJ;Korkie LJ;Mouton J;Riedemann J;Moolman-Smook JC
通讯作者：
Moolman-Smook JC
影响因子：
4.8
作者：
Kugler, Jamie E.;Horsch, Marion;Bustin, Michael
通讯作者：
Bustin, Michael
影响因子：
2.5
作者：
Conforti, L;Buckmaster, EA;Coleman, MP
通讯作者：
Coleman, MP
DUF1220 剂量与自闭症三种主要症状的严重程度线性相关。
影响因子：
4.5
作者：
Davis JM;Searles VB;Anderson N;Keeney J;Dumas L;Sikela JM
通讯作者：
Sikela JM
影响因子：
4.8
作者：
Dumont, Magali;Stack, Cliona;Beal, M. Flint
通讯作者：
Beal, M. Flint