Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition.
Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition.
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DOI：
10.1371/journal.pgen.1006886
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发表时间：
2017-07
期刊：
影响因子：
4.5
通讯作者：
Herault Y
中科院分区：
文献类型：
--
作者：
Arbogast T;Iacono G;Chevalier C;Afinowi NO;Houbaert X;van Eede MC;Laliberte C;Birling MC;Linda K;Meziane H;Selloum M;Sorg T;Nadif Kasri N;Koolen DA;Stunnenberg HG;Henkelman RM;Kopanitsa M;Humeau Y;De Vries BBA;Herault Y
库伦-德弗里斯综合征 (KdVS) 是一种多系统疾病，其特征为智力障碍、友善行为和先天畸形。该综合征是由 17q21.31 染色体区域的微缺失或 KANSL1 基因的变异引起的。相互的 17q21.31 微重复综合征与精神运动迟缓和社交互动减少有关。为了研究 17q21.31 微缺失和微重复综合征的病理生理学，我们生成了三种小鼠模型：1）缺失（Del/+）；或 2) 17q21.31 同线区的相互重复 (Dup/+)； 3) 杂合 Kansl1 (Kans1+/-) 模型。我们发现在 Del/+ 和 Dup/+ 动物中观察到与颅面和大脑结构变化相关的体重、一般活动、社会行为、物体识别和恐惧调节记忆的改变。通过研究海马功能，我们发现 Del/+ 和 Dup/+ 小鼠存在突触传递缺陷。与 Del/+ 小鼠相比，Kansl1 杂合功能丧失突变小鼠表现出相似的行为和解剖表型，但社交表型除外。 Del/+ 和 Kansl1+/- 动物海马中控制染色质组织、突触传递和神经发生的基因上调。我们的结果证明了 KANSL1 在 KdVS 表型表现中的含义，并大大扩展了我们对受这些突变影响的生物过程的了解。 Del/+ 和 Kansl1+/- 小鼠之间的社会行为和基因表达谱存在明显差异，表明受 17q21.31 缺失影响的其他基因的潜在作用。总之，这些新型小鼠模型为治疗方法的开发提供了有价值的新遗传工具。 17q21.31 缺失综合征，也称为 Koolen-de Vries 综合征 (KdVS)，是一种罕见的拷贝数变异，与智力障碍、友善行为和先天畸形等人类相关。该综合征是由 17q21.31 区域的微缺失或人类 KANSL1 基因的变异引起的。倒数 17q21.31 微重复综合征的特征尚不明确。为了研究这些综合征的病理生理学，我们研究了小鼠中同线性区域的缺失、重复和杂合 Kansl1 突变体。我们发现 KdVS 模型的海马体形态和认知受到影响，与人类状况相似，控制染色质组织、突触传递和神经发生的基因失调。此外，我们发现 KdVS 小鼠的突触传递发生了改变。我们的结果证明了 KANSL1 在 KdVS 表现中的含义，并大大扩展了我们对改变的生物过程的认识。尽管如此，缺失模型和 Kansl1+/- 模型之间的表型差异提示了受 17q21.31 缺失影响的其他基因的作用。
Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches. The 17q21.31 deletion syndrome, also named Koolen-de Vries syndrome (KdVS), is a rare copy number variants associated in humans with intellectual disability, friendly behavior, congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 region or by variants in the KANSL1 gene in human. The reciprocal 17q21.31 microduplication syndrome is not so well characterized. To investigate the pathophysiology of the syndromes, we studied the deletion, the duplication of the syntenic region and a heterozygous Kansl1 mutant in the mouse. We found affected morphology and cognition, similar to human condition, with genes controlling chromatin organization, synaptic transmission and neurogenesis dysregulated in the hippocampus of KdVS models. In addition we found that synaptic transmission was altered in KdVS mice. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS and extend substantially our knowledge about altered biological processes. Nevertheless, phenotypic differences between deletion and Kansl1+/- models suggested roles of other genes affected by the 17q21.31 deletion.
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DOI：
10.1093/jnen/63.5.429
发表时间：
2004-05-01
影响因子：
3.2
作者：
Branchi, I;Bichler, Z;Alleva, E
通讯作者：
Alleva, E
影响因子：
6.2
作者：
Griswold AJ;Dueker ND;Van Booven D;Rantus JA;Jaworski JM;Slifer SH;Schmidt MA;Hulme W;Konidari I;Whitehead PL;Cuccaro ML;Martin ER;Haines JL;Gilbert JR;Hussman JP;Pericak-Vance MA
通讯作者：
Pericak-Vance MA
DOI：
10.1002/ajmg.1295
发表时间：
2001-06-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
Boyle, J;Sangha, K;Yong, SL
通讯作者：
Yong, SL
影响因子：
3.5
作者：
Griswold, Anthony J.;Ma, Deqiong;Pericak-Vance, Margaret A.
通讯作者：
Pericak-Vance, Margaret A.
影响因子：
9.8
作者：
Arking, Dan E.;Cutler, David J.;Chakravarti, Aravinda
通讯作者：
Chakravarti, Aravinda