title: A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome.
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.
authors.affiliation: Department of Human Genetics (855), Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO-Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Machteld M
authors.initials: MM
authors.lastname: Oud
authors.affiliation: Laboratory of Human Embryology & Genetics, Institute of Medical Biology, ASTAR, Singapore, Singapore.
authors.forename: Carine
authors.initials: C
authors.lastname: Bonnard
authors.affiliation: Department of Human Genetics (855), Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO-Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Dorus A
authors.initials: DA
authors.lastname: Mans
authors.affiliation: Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Umut
authors.initials: U
authors.lastname: Altunoglu
authors.affiliation: Institute of Molecular and Cell Biology, ASTAR, Singapore, Singapore.
authors.forename: Sumanty
authors.initials: S
authors.lastname: Tohari
authors.affiliation: Institute of Molecular and Cell Biology, ASTAR, Singapore, Singapore.
authors.forename: Alvin Yu Jin
authors.initials: AYJ
authors.lastname: Ng
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, USA.
authors.forename: Ascia
authors.initials: A
authors.lastname: Eskin
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA.
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, University of Western Ontario, Room 4212A, 1151 Richmond Street N, N6A 5B7 London, ON Canada.|Medical Genetics Program, London Health Sciences Centre, London, ON Canada.|Children's Health Research Institute, London, ON Canada.
authors.forename: C Anthony
authors.initials: CA
authors.lastname: Rupar
authors.affiliation: Department of Human Genetics (855), Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO-Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Nathalie P
authors.initials: NP
authors.lastname: de Wagenaar
authors.affiliation: Department of Human Genetics (855), Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO-Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Ka Man
authors.initials: KM
authors.lastname: Wu
authors.affiliation: Department of Paediatrics, The Hospital for Sick Children, Toronto, ON Canada.
authors.forename: Piya
authors.initials: P
authors.lastname: Lahiry
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Pazour
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, USA.|Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: Department of Biochemistry, University of Western Ontario, Room 4212A, 1151 Richmond Street N, N6A 5B7 London, ON Canada.|Robarts Research Institute, London, ON Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.affiliation: Department of Human Genetics (855), Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO-Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.affiliation: Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.|Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey.
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.affiliation: Institute of Molecular and Cell Biology, ASTAR, Singapore, Singapore.
authors.forename: Byrappa
authors.initials: B
authors.lastname: Venkatesh
authors.affiliation: Department of Biochemistry, University of Western Ontario, Room 4212A, 1151 Richmond Street N, N6A 5B7 London, ON Canada.|Medical Genetics Program, London Health Sciences Centre, London, ON Canada.|Children's Health Research Institute, London, ON Canada.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Siu
authors.affiliation: Laboratory of Human Embryology & Genetics, Institute of Medical Biology, ASTAR, Singapore, Singapore.
authors.forename: Bruno
authors.initials: B
authors.lastname: Reversade
authors.affiliation: Department of Human Genetics (855), Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO-Box 9101, 6500 HB Nijmegen, The Netherlands.|Department of Biochemistry, University of Western Ontario, Room 4212A, 1151 Richmond Street N, N6A 5B7 London, ON Canada.|Children's Health Research Institute, London, ON Canada.|Robarts Research Institute, London, ON Canada.
authors.forename: Heleen H
authors.initials: HH
authors.lastname: Arts
keywords: Ciliary defects; Ciliopathy; ECO; Endocrine-cerebro-osteodysplasia syndrome; ICK; Intestinal cell kinase; SRTD; Short-rib thoracic dysplasia syndrome