A Multiplex Human Syndrome Implicates a Key Role for Intestinal Cell Kinase in Development of Central Nervous, Skeletal, and Endocrine Systems

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.

An essential role of intestinal cell kinase in lung development is linked to the perinatal lethality of human ECO syndrome

“…Human endocrine-cerebro-osteodysplasia (ECO) syndrome is an autosomal-recessive neonatal-lethal disorder associated with congenital developmental defects in multiple organ systems [1]. A homozygous loss-of-function mutation R272Q in the human ICK (intestinal cell kinase) gene, encoding a highly conserved and ubiquitously expressed serine/threonine protein kinase [2, 3], was identified as the causative mutation for ECO [1].…”

“…A homozygous loss-of-function mutation R272Q in the human ICK (intestinal cell kinase) gene, encoding a highly conserved and ubiquitously expressed serine/threonine protein kinase [2, 3], was identified as the causative mutation for ECO [1]. ICK is very similar to MAP kinase in the catalytic domain and contains a MAPK-like TDY motif in its activation loop [3, 4].…”

Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key regulator of cilia length and Hedgehog signaling

“…Finally, we examined outcomes of the ICK point mutation (R272Q) identified in human ECO syndrome (1). When mutant versions of ICK (R272A or R272Q) were overexpressed in cultured cells, primary cilia were significantly elongated (Fig.…”

“…Six infants with ECO syndrome from a consanguineous Amish pedigree were observed to have multiple defects including hydrocephalus, holoprosencephaly, agenesis of the diencephalon, adrenal hypoplasia, and skeletal system defects such as cleft lip/palate, postaxial polydactyly, micromelia, hands with ulnar deviation, and bone underdevelopment (1). Genetic analysis of the infants with ECO syndrome revealed a missense mutation in a highly conserved C-terminal basic polar amino acid residue, Arg 272 , to neutral glutamine in the intestinal cell kinase (ICK) gene (1), which impairs the activation and subcellular localization of ICK in cultured cells. How these abnormalities in ICK result in pathological ECO syndrome phenotypes, however, remains unknown.…”

Phenome-Wide Association Studies: Embracing Complexity for Discovery

“…In a different example, 70 phenotypic observations per patient were collected for a study of neonatal disorder with multiple phenotypic features. Hierarchical cluster analyses indicated that the neonatal disorder under study was likely a novel disorder when compared to six related congenital syndromes, and the data suggested a novel molecular mechanism [16,46] .…”