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A Multiplex Human Syndrome Implicates a Key Role for Intestinal Cell Kinase in Development of Central Nervous, Skeletal, and Endocrine Systems |
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| Authors: | Piya Lahiry Jian Wang John F. Robinson Jacob P. Turowec David W. Litchfield Matthew B. Lanktree Gregory B. Gloor Erik G. Puffenberger Kevin A. Strauss Mildred B. Martens David A. Ramsay C. Anthony Rupar Victoria Siu Robert A. Hegele |
| Affiliation: | 1 Robarts Research Institute, London, Ontario N6A 5K8, Canada 2 Department of Biochemistry, University of Western Ontario, London, Ontario N6A 5C1, Canada 3 Clinic for Special Children, Strasburg, PA 17579, USA 4 Department of Pathology, London Health Sciences Centre, London, Ontario N6A 5A5, Canada 5 Medical Genetics Program, London Health Sciences Centre, London, Ontario N6C 2V5, Canada 6 Children's Health Research Institute, London, Ontario N6C 2V5, Canada |
| Abstract: | Six infants in an Old Order Amish pedigree were observed to be affected with endocrine-cerebro-osteodysplasia (ECO). ECO is a previously unidentified neonatal lethal recessive disorder with multiple anomalies involving the endocrine, cerebral, and skeletal systems. Autozygosity mapping and sequencing identified a previously unknown missense mutation, R272Q, in ICK, encoding intestinal cell kinase (ICK). Our results established that R272 is conserved across species and among ethnicities, and three-dimensional analysis of the protein structure suggests protein instability due to the R272Q mutation. We also demonstrate that the R272Q mutant fails to localize at the nucleus and has diminished kinase activity. These findings suggest that ICK plays a key role in the development of multiple organ systems. |
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