CILK1

Cilia effects upon perturbation of CILK1

Cilia number / % ciliated:

Decreased cilia number

Loss-of-function effect:

Shorter cilia

Overexpression effect:

No effect

Phenotypes

Mouse phenotype:

decreased heart rate, preweaning lethality, complete penetrance, increased startle reflex, decreased locomotor activity, decreased grip strength

Human ciliopathy phenotype:

Four diseases by patient-mutation evidence: (1) ECO Syndrome — neonatal-lethal multi-organ developmental defects (endocrine, cerebral, skeletal); polydactyly, short ribs, bowed limbs, abnormal long bones, defective intervertebral disk, reduced mineralization. (2) Short-Rib Polydactyly Syndrome — rhizomelia, mesomelia with bending, polydactyly. (3) Cranioectodermal Dysplasia (Sensenbrenner) — disproportionately short stature, skeletal abnormalities, ectodermal dysplasia, renal failure, liver fibrosis (Kaplan et al. 2025). (4) Juvenile Myoclonic Epilepsy-10 — generalized seizures; heterozygous variants confer susceptibility.

Ciliopathy associations

• Cranioectodermal Dysplasia (Sensenbrenner)
• Endocrine-Cerebro-Osteodysplasia Syndrome
• Juvenile Myoclonic Epilepsy
• Short-Rib Thoracic Dysplasia

References: PMID:27069622, PMID:27466187, PMID:40615527, PMID:29490182, PMID:24853502

Subcellular localization

cilia tip, primary cilium, basal body, intraflagellar transport

References: PMID:24853502, PMID:41005307, PMID:24797473, PMID:25243405, PMID:32732286

Functional category

• Ciliary assembly/disassembly
• Signaling (Hedgehog, GPCRs, ion channels)
• Cilia length regulation

Function

CILK1 (formerly ICK, intestinal cell kinase; HGNC renamed 2019) encodes a serine/threonine kinase with an N-terminal catalytic domain and a C-terminal non-catalytic domain that interacts with the IFT-B complex. CILK1 regulates ciliary length, IFT turnover at the ciliary tip, and Hedgehog signalling via phosphorylation of KIF3A. Four distinct human disease associations have been documented by patient mutations: (1) Endocrine-Cerebro-Osteodysplasia (ECO) Syndrome (OMIM #612651) — biallelic catalytic-domain missense variants (R272Q, G120C, E80K) cause neonatal-lethal ciliopathy with skeletal, cerebral, and endocrine defects (Lahiry 2009; Oud 2016 Cilia journal PMID 27069622); (2) Short-Rib Polydactyly Syndrome — biallelic catalytic-domain variants cause severe skeletal dysplasia (Paige Taylor 2016 PMID 27466187); (3) Cranioectodermal Dysplasia (Sensenbrenner) — homozygous frameshift in the C-terminal non-catalytic domain causes CED in 5 patients from 2 pedigrees with disproportionately short stature, skeletal abnormalities, ectodermal dysplasia, renal failure, and liver complications (Kaplan et al. 2025 Eur J Hum Genet, PMID 40615527); (4) Juvenile Myoclonic Epilepsy-10 (OMIM #617924) — 21 heterozygous variants in 22 of 310 JME patients across 334 families; pathogenic JME variants impair kinase activity (K220E, K305T, A615T, R632X) or cilia length restriction (Bailey 2018 NEJM, PMID 29490182). The CED-causing C-terminal variant reduces cilia number, increases cilia length, and disrupts IFT component localization in patient fibroblasts (Kaplan 2025).