The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by short ribs, shortened long bones, varying types of polydactyly and concomitant visceral abnormalities. Mutations in several genes affecting cilia function cause SRPS, revealing a role for cilia function in skeletal development. To identify additional SRPS genes and discover novel ciliary molecules required for normal skeletogenesis, we performed exome sequencing in a cohort of patients and identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one SRPS family. The p.E80K mutation abolished serine/threonine kinase activity, resulting in altered ICK subcellular and ciliary localization, increased cilia length, aberrant cartilage growth plate structure, defective Hedgehog and altered ERK signalling. These data identify ICK as an SRPS-associated gene and reveal that abnormalities in signalling pathways contribute to defective skeletogenesis.
Bibliographical noteFunding Information:
This work was supported in part by NIH grants RO1 AR066124, R01AR062651, and RO1 DE019567 to D.H.C. and D.K. Sequencing was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grant 2UM1HG006493 to Drs. Debbie Nickerson, Michael Bamshad, and Suzanne Leal. The NIH Training Grant in Genomic Analysis and Interpretation T32 HG002536 supported S.P.T. The work was also supported by the Ministry of Education, Youth and Sports of the Czech Republic (KONTAKT LH12004, LH15231), the Grant Agency of Masaryk University (0071-2013), the European Regional Development Fund (FNUSA-ICR No.CZ.1.05/1.1.00/02.0123; CEITEC No. CZ.1.05/1.100/02.0068) and European Union (ICRCERA-HumanBridge No.316345). A Career Development Grant from the European Organization for Molecular Biology (IG2535) and the Netherlands Organization for Scientific Research (VIDI) supported L.T. L.T. was supported by CEITEC 2020 (LQ1601) project with financial contributions made by the Ministry of Education, Youths and Sports of the Czech Republic within special support paid from the National Programme for Sustainability II funds. Junior researcher funds from the Faculty of Medicine MU supported M.K.B. This research was also supported in part by NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR000124 and by Korea Mouse Phenotyping Project (NRF-2014M3A9D5A01073969) of the Ministry of Science, ICT and Future Planning through the National Research Foundation.
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All Science Journal Classification (ASJC) codes
- Molecular Biology