Publication details

An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome

Authors

TAYLOR S. Paige BOSÁKOVÁ Michaela VAŘECHA Miroslav BÁLEK Lukáš BÁRTA Tomáš TRANTÍREK Lukáš JELÍNKOVÁ Iva DURAN Ivan VESELÁ Iva FORLENZA Kimberly N. MARTIN Jorge H. HAMPL Aleš BAMSHAD Michael NICKERSON Deborah JAWORSKI Margie L. SONG Jieun WAN KO Hyuk COHN Daniel H. KRAKOW Deborah KREJČÍ Pavel

Year of publication 2016
Type Article in Periodical
Magazine / Source Human Molecular Genetics
MU Faculty or unit

Faculty of Medicine

Citation
Doi http://dx.doi.org/10.1093/hmg/ddw240
Field Genetics and molecular biology
Keywords signal transduction; mutation; fibroblast; cartilage; genes; epiphysial cartilage; erinaceidae; homozygote; intestines; phosphotransferases; polydactyly; ribs; short rib-polydactyly syndrome; cilia; long bone; whole exome sequencing
Attached files
Description 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.
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