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首页> 外文期刊>Cilia >A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome
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A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome

机译：一种新的ICK突变导致睫状体破坏和致死性内分泌-脑骨增生综合征

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Background Endocrine-cerebro-osteodysplasia (ECO) syndrome [MIM:612651] caused by a recessive mutation (p.R272Q) in Intestinal cell kinase (ICK) shows significant clinical overlap with ciliary disorders. Similarities are strongest between ECO syndrome, the Majewski and Mohr-Majewski short-rib thoracic dysplasia (SRTD) with polydactyly syndromes, and hydrolethalus syndrome. In this study, we present a novel homozygous ICK mutation in a fetus with ECO syndrome and compare the effect of this mutation with the previously reported ICK variant on ciliogenesis and cilium morphology. Results Through homozygosity mapping and whole-exome sequencing, we identified a second variant (c.358G?>?T; p.G120C) in ICK in a Turkish fetus presenting with ECO syndrome. In vitro studies of wild-type and mutant mRFP-ICK (p.G120C and p.R272Q) revealed that, in contrast to the wild-type protein that localizes along the ciliary axoneme and/or is present in the ciliary base, mutant proteins rather enrich in the ciliary tip. In addition, immunocytochemistry revealed a decreased number of cilia in ICK p.R272Q-affected cells. Conclusions Through identification of a novel ICK mutation, we confirm that disruption of ICK causes ECO syndrome, which clinically overlaps with the spectrum of ciliopathies. Expression of ICK-mutated proteins result in an abnormal ciliary localization compared to wild-type protein. Primary fibroblasts derived from an individual with ECO syndrome display ciliogenesis defects. In aggregate, our findings are consistent with recent reports that show that ICK regulates ciliary biology in vitro and in mice, confirming that ECO syndrome is a severe ciliopathy.
机译：背景肠道细胞激酶（ICK）的隐性突变（p.R272Q）引起的内分泌脑骨增生（ECO）综合征[MIM：612651]显示与睫状疾病显着的临床重叠。 ECO综合征，多指综合征的Majewski和Mohr-Majewski短肋胸廓发育不良（SRTD）与水合综合征之间的相似性最强。在这项研究中，我们提出了一种具有ECO综合征的胎儿中的新型纯合ICK突变，并将该突变与先前报道的ICK变体对纤毛发生和纤毛形态的影响进行了比较。结果通过纯合性作图和全外显子组测序，我们在患有ECO综合征的土耳其胎儿的ICK中鉴定出第二个变异（c.358Gα>ΔT; p.G120C）。对野生型和突变型mRFP-ICK（p.G120C和p.R272Q）的体外研究表明，与沿睫状轴突定位和/或存在于睫状基质中的野生型蛋白相反，突变蛋白相当丰富的睫毛尖端。此外，免疫细胞化学显示，受ICK p.R272Q影响的细胞中纤毛数量减少。结论通过鉴定一个新的ICK突变，我们证实ICK的破坏会导致ECO综合征，该综合征在临床上与纤毛病谱重叠。与野生型蛋白相比，ICK突变蛋白的表达导致睫状体异常定位。源自患有ECO综合征的个体的原代成纤维细胞显示出纤毛生成缺陷。总体而言，我们的发现与最近的报道一致，后者表明ICK在体外和小鼠中调节睫状体生物学，证实ECO综合征是一种严重的纤毛病。

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