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Title: A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome
Authors: Oud, M.M
Bonnard, C
Mans, D.A
Altunoglu, U
Tohari, S
Ng, A.Y.J
Eskin, A
Lee, H
Rupar, C.A
Wagenaar, N.P
Wu, K.M
Lahiry, P
Pazour, G.J
Nelson, S.F
Hegele, R.A
Roepman, R
Kayserili, H
Venkatesh, B 
Siu, V.M
Reversade, B 
Arts, H.H
Keywords: intestinal cell kinase
protein kinase
unclassified drug
animal cell
bone dysplasia
brain disease
case report
cell disruption
controlled study
endocrine cerebroosteodysplasia syndrome
endocrine disease
eukaryotic flagellum
gene mapping
gene mutation
gene sequence
human cell
ICK gene
in vitro study
priority journal
protein localization
Issue Date: 2016
Citation: Oud, M.M, Bonnard, C, Mans, D.A, Altunoglu, U, Tohari, S, Ng, A.Y.J, Eskin, A, Lee, H, Rupar, C.A, Wagenaar, N.P, Wu, K.M, Lahiry, P, Pazour, G.J, Nelson, S.F, Hegele, R.A, Roepman, R, Kayserili, H, Venkatesh, B, Siu, V.M, Reversade, B, Arts, H.H (2016). A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome. Cilia 5 (1) : 8. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: 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. © 2016 Oud et al.
Source Title: Cilia
ISSN: 20462530
DOI: 10.1186/s13630-016-0029-1
Rights: Attribution 4.0 International
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