DUF1220 dosage is linearly associated with increasing severity of the three primary symptoms of autism.
DUF1220 dosage is linearly associated with increasing severity of the three primary symptoms of autism.
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DUF1220 剂量与自闭症三种主要症状的严重程度线性相关。
DOI：
10.1371/journal.pgen.1004241
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发表时间：
2014-03
期刊：
影响因子：
4.5
通讯作者：
Sikela JM
中科院分区：
文献类型：
--
作者：
Davis JM;Searles VB;Anderson N;Keeney J;Dumas L;Sikela JM
与自闭症谱系障碍(ASD)相关的三个最常见的拷贝数变异之一是1q21.1重复，它包含编码DUF1220蛋白结构域的序列，我们之前曾认为DUF1220的剂量与人脑大小有关。此外，ASD患者经常表现出大脑生长加速和大脑更大，这也与症状严重程度增加有关。鉴于这些发现，我们调查了DUF1220拷贝数与ASD严重程度之间的关系，并在此表明，在ASD患者(n = 170)中，DUF1220亚型CON1的拷贝数(剂量)是高度可变的，范围从56到88个拷贝服从高斯分布。更值得注意的是，在自闭症患者中，CON1拷贝数也以剂量-反应方式与自闭症三种主要症状的严重程度的增加呈线性相关：社交缺陷(p = 0.021)、沟通障碍(p = 0.030)和重复行为(p = 0.047)。这些数据表明，DUF1220蛋白结构域(CON1)的剂量对ASD具有广泛的影响，因此很可能是导致ASD严重程度的主要途径的关键组成部分。最后，这些发现通过暗示先前未被检查的、拷贝数多态和脑进化相关的基因编码序列在ASD严重程度中的剂量，为进一步研究ASD背后的遗传因素提供了重要的新方向。自闭症谱系障碍(ASD)是一种常见的行为定义的疾病，表现为社会互惠和沟通能力的损害，以及夸张的重复行为和刻板印象的兴趣。与正常发育的同龄人相比，自闭症患者的大脑通常更大，生长更快。鉴于广泛记载的遗传力表明ASD主要是一种遗传疾病，以及ASD与异常脑生长模式之间已确立的联系，参与脑生长的基因将是研究ASD的极佳候选基因。DUF1220就是这样的候选基因之一，它是一个高拷贝数的多态蛋白结构域，我们之前已经将其与大脑进化和大脑大小联系在一起。然而，由于DUF1220的极端拷贝数变异性，在以往寻找ASD重要基因的全基因组多态研究中尚未对其进行直接研究。在这里，我们发现，在ASD患者中，1)DUF1220亚型CON1是高度可变的，从56到88个拷贝，以及2)CON1的拷贝数以线性剂量-反应方式与ASD的三个主要症状中的每一个的严重程度增加相关：随着CON1拷贝数的增加，ASD的三个主要症状(社交互惠能力受损、沟通能力受损和重复行为增加)逐渐恶化。
One of the three most frequently documented copy number variations associated with autism spectrum disorder (ASD) is a 1q21.1 duplication that encompasses sequences encoding DUF1220 protein domains, the dosage of which we previously implicated in increased human brain size. Further, individuals with ASD frequently display accelerated brain growth and a larger brain size that is also associated with increased symptom severity. Given these findings, we investigated the relationship between DUF1220 copy number and ASD severity, and here show that in individuals with ASD (n = 170), the copy number (dosage) of DUF1220 subtype CON1 is highly variable, ranging from 56 to 88 copies following a Gaussian distribution. More remarkably, in individuals with ASD CON1 copy number is also linearly associated, in a dose-response manner, with increased severity of each of the three primary symptoms of ASD: social deficits (p = 0.021), communicative impairments (p = 0.030), and repetitive behaviors (p = 0.047). These data indicate that DUF1220 protein domain (CON1) dosage has an ASD-wide effect and, as such, is likely to be a key component of a major pathway underlying ASD severity. Finally, these findings, by implicating the dosage of a previously unexamined, copy number polymorphic and brain evolution-related gene coding sequence in ASD severity, provide an important new direction for further research into the genetic factors underlying ASD. Autism Spectrum Disorder (ASD) is a common behaviorally defined condition noted by impairments in social reciprocity and communicative abilities and exaggerated repetitive behaviors and stereotyped interests. Individuals with ASD frequently have a larger and more rapidly growing brain than their typically developing peers. Given the widely documented heritability suggesting that ASD is predominantly a genetic condition and the well-established link between ASD and abnormal brain growth patterns, genes involved in brain growth would be excellent candidates to study regarding ASD. One such candidate is DUF1220, a highly copy number polymorphic protein domain that we have previously linked to brain evolution and brain size. However, due to the extreme copy number variability of DUF1220, it has not been directly investigated in previous genome wide polymorphism studies searching for genes important in ASD. Here we show that, in individuals with ASD, 1) DUF1220 subtype CON1 is highly variable, ranging from 56 to 88 copies, and 2) the copy number of CON1 is associated, in a linear dose-response manner, with increased severity of each of the three primary symptoms of ASD: as CON1 copy number increases each of the three primary symptoms of ASD (impaired social reciprocity, impaired communicative ability and increased repetitive behaviors) become incrementally worse.
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影响因子：
4.4
作者：
Rojas, Donald C;Peterson, Eric;Winterrowd, Erin;Reite, Martin L;Rogers, Sally J;Tregellas, Jason R
通讯作者：
Tregellas, Jason R
DOI：
10.1038/nrg3336
发表时间：
2012-12
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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DOI：
10.1176/appi.ajp.2010.09101470
发表时间：
2010-11
期刊：
The American journal of psychiatry
影响因子：
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作者：
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通讯作者：
Law P
影响因子：
6.4
作者：
Nordenbaek, Claudia;Jorgensen, Meta;Bilenberg, Niels
通讯作者：
Bilenberg, Niels
影响因子：
10.6
作者：
Schumann, Cynthia Mills;Barnes, Cynthia Carter;Courchesne, Eric
通讯作者：
Courchesne, Eric