A Multiplex Human Syndrome Implicates a Key Role for Intestinal Cell Kinase in Development of Central Nervous, Skeletal, and Endocrine Systems
A Multiplex Human Syndrome Implicates a Key Role for Intestinal Cell Kinase in Development of Central Nervous, Skeletal, and Endocrine Systems
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DOI：
10.1016/j.ajhg.2008.12.017
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发表时间：
2009-02-13
影响因子：
9.8
通讯作者：
Hegele, Robert A.
中科院分区：
文献类型：
--
作者：
Lahiry, Piya;Wang, Jian;Hegele, Robert A.
在一个古老的阿米什人家系中，观察到6名婴儿患有内分泌-脑-骨发育不良（ECO）。ECO是一种以前未发现的新生儿致死性隐性疾病，具有涉及内分泌、大脑和骨骼系统的多种异常。同源性定位和测序鉴定了一个以前未知的错义突变，R272 Q，在ICK，编码肠细胞激酶（ICK）。我们的研究结果表明，R272在不同物种和种族之间是保守的，蛋白质结构的三维分析表明，由于R272 Q突变，蛋白质不稳定。我们还表明，R272 Q突变体未能定位在细胞核和激酶活性降低。这些发现表明，ICK在发展中起着关键作用，
Six infants in an Old Order Amish pedigree were observed to be affected with endocrine-cerebro-osteodysplasia (ECO). ECO is a previously unidentified neonatal lethal recessive disorder with multiple anomalies involving the endocrine, cerebral, and skeletal systems. Autozygosity mapping and sequencing identified a previously unknown missense mutation, R272Q, in ICK, encoding intestinal cell kinase (ICK). Our results established that R272 is conserved across species and among ethnicities, and three-dimensional analysis of the protein structure suggests protein instability due to the R272Q mutation. We also demonstrate that the R272Q mutant fails to localize at the nucleus and has diminished kinase activity. These findings suggest that ICK plays a key role in the development of