title: An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome.
abstract: 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.
authors.affiliation: Department of Human Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: S
authors.initials: S
authors.lastname: Paige Taylor
authors.affiliation: Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kunova Bosakova
authors.affiliation: Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Varecha
authors.affiliation: Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Balek
authors.affiliation: Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Barta
authors.affiliation: Central European Institute of Technology, Masaryk University, Kamenice 753/5, 62500 Brno, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Trantirek
authors.affiliation: Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
authors.forename: Iva
authors.initials: I
authors.lastname: Jelinkova
authors.affiliation: Department of Orthopaedic Surgery.|Department of Human Genetics.|Department of Obstetrics and Gynecology, Orthopaedic Institute for Children, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Duran
authors.affiliation: Institute of Experimental Biology, Masaryk University, 62500 Brno, Czech Republic.
authors.forename: Iva
authors.initials: I
authors.lastname: Vesela
authors.affiliation: Department of Orthopaedic Surgery.|Department of Human Genetics.|Department of Obstetrics and Gynecology, Orthopaedic Institute for Children, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Forlenza
authors.affiliation: Department of Orthopaedic Surgery.|Department of Human Genetics.|Department of Obstetrics and Gynecology, Orthopaedic Institute for Children, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Martin
authors.affiliation: Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
authors.forename: Ales
authors.initials: A
authors.lastname: Hampl
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.|Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.|Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bamshad
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Nickerson
authors.affiliation: Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Margie L
authors.initials: ML
authors.lastname: Jaworski
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Goyang 410-820, Korea.
authors.forename: Jieun
authors.initials: J
authors.lastname: Song
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Goyang 410-820, Korea.
authors.forename: Hyuk Wan
authors.initials: HW
authors.lastname: Ko
authors.affiliation: Department of Orthopaedic Surgery.|International Skeletal Dysplasia Registry, University of California Los Angeles, Los Angeles, CA 90095, USA.|Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.affiliation: Department of Human Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA DKrakow@mednet.ucla.edu.|Department of Orthopaedic Surgery.|International Skeletal Dysplasia Registry, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.affiliation: Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.|Department of Orthopaedic Surgery.|International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Krejci
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D002923:Cilia / Q000235:genetics / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D020935:MAP Kinase Signaling System; D010375:Pedigree; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012779:Short Rib-Polydactyly Syndrome / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D012863:Skeleton / Q000002:abnormalities / Q000254:growth & development*
chemical_list: D053823:Hedgehog Proteins; C097276:CILK1 protein, human; D017346:Protein Serine-Threonine Kinases