Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome.
Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome.
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DOI：
10.1371/journal.pgen.1000650
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发表时间：
2009-09
期刊：
影响因子：
4.5
通讯作者：
Lander AD
中科院分区：
文献类型：
--
作者：
Kawauchi S;Calof AL;Santos R;Lopez-Burks ME;Young CM;Hoang MP;Chua A;Lao T;Lechner MS;Daniel JA;Nussenzweig A;Kitzes L;Yokomori K;Hallgrimsson B;Lander AD
科尔内利亚德兰格综合征（CdLS）是一种多器官系统出生缺陷疾病，至少有一半的病例与NIPBL基因的杂合突变有关。在动物和真菌中，NIPBL的直系同源物调节粘着蛋白，这是一种蛋白质复合物，对染色体粘着至关重要，也涉及DNA修复和转录调节。产生了Nipbl中基因陷阱突变的杂合小鼠，并表现出CdLS特征性缺陷，包括小尺寸、颅面异常、微短头畸形、心脏缺陷、听力异常、骨成熟延迟、体脂减少、行为障碍和生命最初几周内的高死亡率（75-80%）。尽管Nipbl转录水平仅下降了约30%，这些表型还是出现了，这意味着发育对Nipbl活性的微小变化极其敏感。基因表达谱分析表明，Nipbl缺陷导致许多基因的适度但显著的转录失调。在原钙粘蛋白β（Pcdhb）基因座，以及在其他基因座的表达变化，支持NIPBL影响长距离染色体调控相互作用的观点。此外，有证据表明，参与脂肪形成分化的基因表达减少可能是在Nipbl+/−小鼠和CdLS个体中观察到的低体脂量的基础。科尔内利亚德兰格综合征（CdLS）是一种遗传性疾病，其特征是生长迟缓、认知和神经问题以及许多器官系统的结构缺陷。大多数CdLS病例是由于一个拷贝的Nipped B样（NIPBL）基因突变所致，该基因的产物调节一种称为粘附素的染色体蛋白复合物。NIPBL功能的降低如何引起CdLS中的普遍发育缺陷尚不清楚，因此通过产生携带Nipbl的一个无效等位基因的小鼠来开发CdLS模型。这些小鼠的发育缺陷与在CdLS个体中观察到的发育缺陷非常相似，包括身材矮小、颅面异常、体脂减少、行为障碍和围产期死亡率高。Nipbl突变小鼠的组织和细胞的分子分析提供了第一个证据，即Nipbl在CdLS的病因学中的主要作用是对不同基因组的表达施加适度但显著的影响，其中一些基因组位于DNA的特征性排列沿着。在受影响的基因中，有一组涉及脂肪细胞的发育，脂肪细胞是制造和积累体脂的细胞，这可能解释了在CdLS患者中常见的体脂积累减少。
Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75–80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only ∼30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/− mice and in individuals with CdLS. Cornelia de Lange Syndrome (CdLS) is a genetic disease marked by growth retardation, cognitive and neurological problems, and structural defects in many organ systems. The majority of CdLS cases are due to mutation of one copy of the Nipped B-like (NIPBL) gene, the product of which regulates a complex of chromosomal proteins called cohesin. How reduction of NIPBL function gives rise to pervasive developmental defects in CdLS is not understood, so a model of CdLS was developed by generating mice that carry one null allele of Nipbl. Developmental defects in these mice show remarkable similarity to those observed in individuals with CdLS, including small stature, craniofacial abnormalities, reduced body fat, behavioral disturbances, and high perinatal mortality. Molecular analysis of tissues and cells from Nipbl mutant mice provide the first evidence that the major role of Nipbl in the etiology of CdLS is to exert modest, but significant, effects on the expression of diverse sets of genes, some of which are located in characteristic arrangements along the DNA. Among affected genes is a set involved in the development of adipocytes, the cells that make and accumulate body fat, potentially explaining reductions in body fat accumulation commonly observed in individuals with CdLS.
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DOI：
10.1111/j.1749-6632.2008.03450.x
发表时间：
2009-01-01
期刊：
YEAR IN HUMAN AND MEDICAL GENETICS 2009
影响因子：
--
作者：
Dorsett, Dale;Krantz, Ian D.
通讯作者：
Krantz, Ian D.
DOI：
10.1073/pnas.97.24.13384
发表时间：
2000-11-21
影响因子：
11.1
作者：
Contos, JJA;Fukushima, N;Chun, J
通讯作者：
Chun, J
影响因子：
6.5
作者：
Abderrahim-Ferkoune, A;Bezy, O;Amri, EZ
通讯作者：
Amri, EZ
影响因子：
16.2
作者：
Chang, QA;Khare, G;Jaenisch, R
通讯作者：
Jaenisch, R
影响因子：
4.6
作者：
Dorsett, D;Eissenberg, JC;McKim, K
通讯作者：
McKim, K