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

University of Washington Center for Mendelian Genomics

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3998-4011
Number of pages14
JournalHuman molecular genetics
Volume25
Issue number18
DOIs
Publication statusPublished - 2016 Jan 1

Fingerprint

Short Rib-Polydactyly Syndrome
Phosphotransferases
Cilia
Mutation
Genes
Exome
Polydactyly
Growth Plate
Protein-Serine-Threonine Kinases
Ribs
Missense Mutation
Cartilage
Bone and Bones

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

University of Washington Center for Mendelian Genomics. / An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome. In: Human molecular genetics. 2016 ; Vol. 25, No. 18. pp. 3998-4011.
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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.",
author = "{University of Washington Center for Mendelian Genomics} and Taylor, {S. Paige} and Bosakova, {Michaela Kunova} and Miroslav Varecha and Lukas Balek and Tomas Barta and Lukas Trantirek and Iva Jelinkova and Ivan Duran and Iva Vesela and Forlenza, {Kimberly N.} and Martin, {Jorge H.} and Ales Hampl and Michael Bamshad and Deborah Nickerson and Jaworski, {Margie L.} and Jieun Song and Ko, {Hyuk Wan} and Cohn, {Daniel H.} and Deborah Krakow and Pavel Krejci",
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An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome. / University of Washington Center for Mendelian Genomics.

In: Human molecular genetics, Vol. 25, No. 18, 01.01.2016, p. 3998-4011.

Research output: Contribution to journalArticle

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T1 - An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome

AU - University of Washington Center for Mendelian Genomics

AU - Taylor, S. Paige

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AU - Varecha, Miroslav

AU - Balek, Lukas

AU - Barta, Tomas

AU - Trantirek, Lukas

AU - Jelinkova, Iva

AU - Duran, Ivan

AU - Vesela, Iva

AU - Forlenza, Kimberly N.

AU - Martin, Jorge H.

AU - Hampl, Ales

AU - Bamshad, Michael

AU - Nickerson, Deborah

AU - Jaworski, Margie L.

AU - Song, Jieun

AU - Ko, Hyuk Wan

AU - Cohn, Daniel H.

AU - Krakow, Deborah

AU - Krejci, Pavel

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AB - 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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