A multiplex human syndrome implicates a key role for intestinal cell kinase in development of central nervous, skeletal, and endocrine systems.
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.
Lahiry
Piya
P
Robarts Research Institute, London, Ontario N6A 5K8, Canada.
Wang
Jian
J
Robinson
John F
JF
Turowec
Jacob P
JP
Litchfield
David W
DW
Lanktree
Matthew B
MB
Gloor
Gregory B
GB
Puffenberger
Erik G
EG
Strauss
Kevin A
KA
Martens
Mildred B
MB
Ramsay
David A
DA
Rupar
C Anthony
CA
Siu
Victoria
V
Hegele
Robert A
RA
D000818:Animals; D001344:Autopsy; D001847:Bone Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000201:enzymology; D002493:Central Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D017124:Conserved Sequence; D004700:Endocrine System Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005006:Ethnicity / Q000235:genetics*; D005091:Exons; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008297:Male; D009154:Mutation; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000097:blood / Q000235:genetics*; D035781:Siblings; D013045:Species Specificity; D013577:Syndrome
C097276:CILK1 protein, human; D017346:Protein Serine-Threonine Kinases