2. Academic Validation
  3. A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome

A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome

  • Cilia. 2016 Apr 11:5:8. doi: 10.1186/s13630-016-0029-1.
Machteld M Oud # 1,  Carine Bonnard # 2,  Dorus A Mans # 1,  Umut Altunoglu 3,  Sumanty Tohari 4,  Alvin Yu Jin Ng 4,  Ascia Eskin 5,  Hane Lee 6,  C Anthony Rupar 7 8 9,  Nathalie P de Wagenaar 1,  Ka Man Wu 1,  Piya Lahiry 10,  Gregory J Pazour 11,  Stanley F Nelson 5 6,  Robert A Hegele 7 12,  Ronald Roepman 1,  Hülya Kayserili 3 13,  Byrappa Venkatesh 4,  Victoria M Siu 7 8 9,  Bruno Reversade # 2,  Heleen H Arts # 1 7 9 12
Affiliations

Affiliations

  • 1 Department of Human Genetics (855), Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO-Box 9101, 6500 HB Nijmegen, The Netherlands.
  • 2 Laboratory of Human Embryology & Genetics, Institute of Medical Biology, ASTAR, Singapore, Singapore.
  • 3 Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
  • 4 Institute of Molecular and Cell Biology, ASTAR, Singapore, Singapore.
  • 5 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, USA.
  • 6 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA.
  • 7 Department of Biochemistry, University of Western Ontario, Room 4212A, 1151 Richmond Street N, N6A 5B7 London, ON Canada.
  • 8 Medical Genetics Program, London Health Sciences Centre, London, ON Canada.
  • 9 Children's Health Research Institute, London, ON Canada.
  • 10 Department of Paediatrics, The Hospital for Sick Children, Toronto, ON Canada.
  • 11 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA USA.
  • 12 Robarts Research Institute, London, ON Canada.
  • 13 Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey.
  • # Contributed equally.
PMID: 27069622 DOI: 10.1186/s13630-016-0029-1
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.

Keywords

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

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