A p.D116G mutation in CREB1 leads to novel multiple malformation syndrome resembling CrebA knockout mouse
A p.D116G mutation in CREB1 leads to novel multiple malformation syndrome resembling CrebA knockout mouse
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DOI：
10.1002/humu.22027
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发表时间：
2012-04-01
期刊：
影响因子：
3.9
通讯作者：
Kitazawa, Riko
中科院分区：
文献类型：
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作者：
Kitazawa, Sohei;Kondo, Takeshi;Kitazawa, Riko
我们评估了一例严重的新生儿呼吸窘迫，胸腺、甲状腺和小脑发育不良的尸检病例，以及显示出与Creba基因敲除小鼠惊人的表型相似的穹窿发育不全。在假设一定存在类似的遗传变化的情况下，我们检查了环磷酸腺苷(CAMP)反应元件结合蛋白1(CREB1)的整个基因组DNA序列，并在CREB1的激酶诱导结构域(KID)内发现了对应于p.D116G的错义C.347A和GT；G突变。当体外转录时，突变的CREB1蛋白不能与共激活因子CREBBP/EP300的KIX结构域结合，从而以显性-阴性形式中断cAMP依赖的蛋白激酶A信号转导，而Forsklin处理保持了KID的Ser-133磷酸化。这是散发性CREB1相关多发性畸形综合征的第一个报告，根据对基因靶标动物表型特征的积累知识，明确强调了跨物种翻译研究的重要性。哼唱，2012年33：651654。(C)2012年威利期刊公司。
We evaluated an autopsy case with severe neonatal respiratory distress, hypoplasia of thymus, thyroid gland and cerebellum, and agenesis of the corpus callosum displaying striking phenotypic similarity to the CrebA knockout mouse. On the assumption that comparable genetic alterations must be present, we checked the whole genomic DNA sequence of cyclic adenosine monophosphate (cAMP) response element binding protein 1 (CREB1), the human counterpart of mouse CrebA, and found a missense c.347A>G mutation corresponding to p.D116G within the kinase-inducible domain (KID) of CREB1. When transcribed in vitro, while Ser-133 phosphorylation of KID was maintained upon forskolin treatment, mutated CREB1 protein failed to associate with the KIX domain of co-activator CREBBP/EP300, and thereby, interrupted cAMP-dependent protein kinase A signal transduction as the dominant-negative form. This is the first report of a sporadic CREB1-related multiple malformation syndrome that, in light of accumulated knowledge of phenotypic features in gene-targeted animals, clearly emphasizes the importance of cross-species translational research. Hum Mutat 33:651654, 2012. (c) 2012 Wiley Periodicals, Inc.