Novel ENU-Induced Mutation in Tbx6 Causes Dominant Spondylocostal Dysostosis-Like Vertebral Malformations in the Rat.
Novel ENU-Induced Mutation in Tbx6 Causes Dominant Spondylocostal Dysostosis-Like Vertebral Malformations in the Rat.
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DOI：
10.1371/journal.pone.0130231
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Mashimo T
中科院分区：
文献类型：
--
作者：
Abe K;Takamatsu N;Ishikawa K;Tsurumi T;Tanimoto S;Sakurai Y;Lisse TS;Imai K;Serikawa T;Mashimo T
由胚胎分节缺陷引起的先天性脊椎畸形在人类和家畜中相对常见。虽然小鼠的反向遗传学方法提供了胚胎体节分割的分子机制的信息，假设驱动的方法不能充分反映人口中的人类畸形。在京都的N-乙基-N-亚硝基脲（ENU）诱变项目中，由于尾椎短而扭结的表型，分离出Oune突变大鼠品系。杂合子大鼠的Skeleton染色显示颈椎部分缺失以及腰椎和骶椎的半椎体和融合椎体块。在纯合子胚胎中，观察到整个椎骨严重移位。使用202个回交动物和50个全基因组微卫星标记将Oune基因座遗传定位于大鼠1号染色体。随后，在Tbx 6基因的错义突变被确定在关键区域。虽然突变位于预测的二聚体界面附近的T-box结构域内，但体外实验表明，Tbx 6变体保留了正常的DNA结合能力和翻译效率。然而，该变体响应于Notch介导的信号传导具有降低的转录激活潜力。最近，有报道称家族性脊椎肋骨发育不全的一种显性类型是由TBX 6的stoploss突变引起的。因此，我们认为Tbx 6的部分功能障碍会导致人类和大鼠类似的先天性脊椎畸形。Oune品系可能是显性脊椎肋骨发育不全的独特动物模型，并可用于人类先天性脊椎畸形病理学的分子解剖。
Congenital vertebral malformations caused by embryonic segmentation defects are relatively common in humans and domestic animals. Although reverse genetics approaches in mice have provided information on the molecular mechanisms of embryonic somite segmentation, hypothesis-driven approaches cannot adequately reflect human dysmorphology within the population. In a N-ethyl-N-nitrosourea (ENU) mutagenesis project in Kyoto, the Oune mutant rat strain was isolated due to a short and kinked caudal vertebra phenotype. Skeletal staining of heterozygous rats showed partial loss of the cervical vertebrae as well as hemivertebrae and fused vertebral blocks in lumbar and sacral vertebrae. In homozygous embryos, severe displacement of the whole vertebrae was observed. The Oune locus was genetically mapped to rat chromosome 1 using 202 backcross animals and 50 genome-wide microsatellite markers. Subsequently, a miss-sense mutation in the Tbx6 gene was identified in the critical region. Although the mutation is located within the T-box domain near a predicted dimmer-interface, in vitro experiments revealed that the Tbx6 variant retains normal DNA binding ability and translational efficiency. However, the variant has decreased transcriptional activation potential in response to Notch-mediated signaling. Recently, it was reported that a dominant type of familial spondylocostal dysostosis is caused by a stoploss mutation in TBX6. Thus, we propose that partial dysfunction of Tbx6 leads to similar congenital vertebral malformations in both humans and rats. The Oune strain could be a unique animal model for dominant spondylocostal dysostosis and is useful for molecular dissection of the pathology of congenital vertebral malformations in humans.
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影响因子：
10.7
作者：
Ahn, Daegwon;You, Kwan-Hee;Kim, Cheol-Hee
通讯作者：
Kim, Cheol-Hee
影响因子：
64.5
作者：
Hsu PD;Lander ES;Zhang F
通讯作者：
Zhang F
影响因子：
2.7
作者：
Chapman, DL;Agulnik, I;Papaioannou, VE
通讯作者：
Papaioannou, VE
DOI：
10.1046/j.1432-1327.2000.01499.x
发表时间：
2000-08-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Kojima, M;Takamatsu, N;Shiba, T
通讯作者：
Shiba, T
影响因子：
5.9
作者：
RIMOIN, DL;FLETCHER, BD;MCKUSICK, VA
通讯作者：
MCKUSICK, VA