Oud Machteld M, Bonnard Carine, Mans Dorus A, Altunoglu Umut, Tohari Sumanty, Ng Alvin Yu Jin, Eskin Ascia, Lee Hane, Rupar C Anthony, de Wagenaar Nathalie P, Wu Ka Man, Lahiry Piya, Pazour Gregory J, Nelson Stanley F, Hegele Robert A, Roepman Ronald, Kayserili Hülya, Venkatesh Byrappa, Siu Victoria M, Reversade Bruno, Arts Heleen H
Department of Human Genetics (855), Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO-Box 9101, 6500 HB Nijmegen, The Netherlands.
Laboratory of Human Embryology & Genetics, Institute of Medical Biology, ASTAR, Singapore, Singapore.
Cilia. 2016 Apr 11;5:8. doi: 10.1186/s13630-016-0029-1. eCollection 2016.
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.
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.
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.
由肠细胞激酶（ICK）中的隐性突变（p.R272Q）引起的内分泌 - 脑 - 骨发育异常（ECO）综合征[MIM:612651]与纤毛病表现出显著的临床重叠。ECO综合征、伴有多指畸形综合征的马耶夫斯基和莫尔 - 马耶夫斯基短肋胸廓发育不良（SRTD）以及水致死性综合征之间的相似性最为明显。在本研究中，我们在一名患有ECO综合征的胎儿中发现了一种新的ICK纯合突变，并将该突变的影响与先前报道的ICK变体对纤毛发生和纤毛形态的影响进行了比较。
通过纯合性定位和全外显子组测序，我们在一名表现出ECO综合征的土耳其胎儿中鉴定出ICK中的另一种变体（c.358G>T；p.G120C）。对野生型和突变型mRFP-ICK（p.G120C和p.R272Q）的体外研究表明，与定位于纤毛轴丝或存在于纤毛基部的野生型蛋白不同，突变蛋白更多地富集在纤毛尖端。此外，免疫细胞化学显示ICK p.R272Q影响的细胞中纤毛数量减少。
通过鉴定一种新的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纤毛定位异常。源自患有ECO综合征个体的原代成纤维细胞表现出纤毛发生缺陷。总的来说，我们的发现与最近的报告一致，这些报告表明ICK在体外和小鼠中调节纤毛生物学，证实ECO综合征是一种严重的纤毛病。
