UMMS Affiliation

Program in Molecular Medicine

Date

4-11-2016

Document Type

Article

Disciplines

Cell Biology | Cellular and Molecular Physiology | Developmental Biology | Genetics and Genomics

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.

Rights and Permissions

Citation: Cilia. 2016 Apr 11;5:8. doi: 10.1186/s13630-016-0029-1. eCollection 2016. Link to article on publisher's site

DOI of Published Version

10.1186/s13630-016-0029-1

Comments

Full author list omitted for brevity. For full list of authors see article.

Related Resources

Link to Article in PubMed

Keywords

Ciliary defects, Ciliopathy, ECO, Endocrine-cerebro-osteodysplasia syndrome, ICK, Intestinal cell kinase, SRTD, Short-rib thoracic dysplasia syndrome

Journal Title

Cilia

PubMed ID

27069622

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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