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

作者：Taylor S Paige; Bosakova Michaela Kunova; Varecha Miroslav; Balek Lukas; Barta Tomas; Trantirek Lukas; Jelinkova Iva; Duran Ivan; Vesela Iva; Forlenza Kimberly N; Martin Jorge H; Hampl Ales; Bamshad Michael; Nickerson Deborah; Jaworski Margie L; Song Jieun; Ko Hyuk Wan; Cohn Daniel H; Krakow Deborah; Krejci Pavel

来源：Human Molecular Genetics, 2016, 25(18): 3998-4011.

DOI：10.1093/hmg/ddw240

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.

• 出版日期2016-9-15