| CEP164 |
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| Symbol | CEP164 |
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| Full Name | Centrosomal Protein 164 |
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| Chromosome | 11q13.2 |
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| NCBI Gene ID | 55107 |
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| OMIM | 614848 |
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| Ensembl | ENSG00000110237 |
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| UniProt | Q8WU02 |
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| Associated Diseases | [Nephronophthisis](/diseases/nephronophthisis), [Joubert syndrome](/diseases/joubert-syndrome), [Senior-Loken syndrome](/diseases/senior-loken-syndrome) |
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CEP164 (Centrosomal Protein 164) is a critical component of the centrosome and primary cilia, serving as a master regulator of ciliogenesis and cell cycle progression graber2007. Located at the distal appendages of the mother centriole, CEP164 functions as a molecular scaffold that recruits essential ciliary proteins and coordinates vesicle trafficking to the forming cilium gomez-ferrero2012.
Beyond its ciliary functions, CEP164 plays a vital role in the DNA damage response through ATM-dependent signaling burke2014. Mutations in CEP164 cause nephronophthisis (NPHP) and related ciliopathies, while emerging research suggests connections between ciliary dysfunction and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease yuan2019, cheng2019.
¶ Gene and Protein Structure
The CEP164 gene is located on chromosome 11q13.2 and encodes a protein of 1463 amino acids with a molecular weight of approximately 164 kDa. The gene contains 37 exons and spans approximately 26 kb of genomic DNA.
¶ Protein Domains
The CEP164 protein contains several functional domains:
- N-terminal coiled-coil domain: Mediates protein-protein interactions and dimerization
- Central proline-rich region: Contains potential phosphorylation sites
- C-terminal domains: Responsible for centriolar localization and microtubule binding
- WD40 repeat region: Functions in protein-protein interactions
flowchart TD
A["Mother Centriole"] --> B["Distal Appendages"]
B --> C["CEP164 Localization"]
C --> D["Ciliary Vesicle Docking"]
C --> E["Centrosome Maturation"]
D --> F["Primary Cilium Formation"]
E --> G["Cell Cycle Progression"]
CEP164 is essential for primary cilia formation siller2017:
- Distal appendage anchoring: CEP164 localizes to the distal appendages of the mother centriole
- Vesicle recruitment: Recruits ciliary vesicles to the centrosome
- Membrane docking: Facilitates fusion of vesicles with the plasma membrane
- Axoneme extension: Supports elongation of the ciliary axoneme
CEP164 regulates cell cycle progression through multiple mechanisms tooley2011:
- Centrosome maturation: Promotes centrosome separation and maturation
- Spindle assembly: Ensures proper mitotic spindle formation
- G1/S transition: Controls entry into S phase
- G2/M checkpoint: Participates in DNA damage checkpoints
CEP164 participates in ATM-mediated DNA damage response burke2014:
- ATM phosphorylation of CEP164 at serine 328
- Recruitment of DNA repair proteins to damage sites
- Cell cycle arrest upon DNA damage
- Connection to p53 tumor suppressor pathway
Primary cilia serve as signaling hubs satir2010, potter2011:
| Pathway |
Function |
Neuronal Relevance |
| Hedgehog |
Development, cell fate |
Neurogenesis |
| Wnt |
Planar cell polarity |
Brain patterning |
| PDGF |
Cell proliferation |
Neurogenesis |
| Notch |
Cell fate decisions |
Differentiation |
Emerging evidence links ciliary dysfunction to Alzheimer's disease yuan2019:
- Centrosome abnormalities: Altered centrosome morphology in AD brain
- Ciliary signaling disruption: Impaired Hedgehog and Wnt signaling
- Cell cycle re-entry: Neurons attempt to re-enter cell cycle
- DNA damage accumulation: Impaired DNA repair in neurons
The centrosome plays critical roles in:
- Neuronal polarity establishment
- Axonal transport
- Synaptic function
- Protein trafficking
Ciliary dysfunction may contribute to Parkinson's disease cheng2019:
- Primary cilia in dopaminergic neurons: Cilia regulate dopamine signaling
- Ciliary signaling disruption: Hedgehog pathway alterations
- Cellular stress response: Cilia as mechanosensors
- Autophagy-lysosomal pathways: Connection to protein aggregation
- Huntington's disease: Ciliary dysfunction in striatal neurons
- Amyotrophic lateral sclerosis: Altered centrosome function in motor neurons
- Retinal degeneration: CEP164 mutations affect photoreceptor cilia
CEP164 mutations cause NPHP chaki2012, a recessive cystic kidney disease:
- NPHP type 15: CEP164 is the causative gene
- Kidney pathology: Tubulointerstitial fibrosis, cyst formation
- Age of onset: Childhood to adolescence
- Extra-renal manifestations: Include neurological symptoms
CEP164 variants can cause this syndrome:
- NPHP combined with retinal dystrophy
- Neurological involvement: Developmental delay, ataxia
- Treatment: Kidney transplant for ESRD
Some CEP164 variants are associated with Joubert syndrome:
- Molar tooth sign on MRI
- Cerebellar and brainstem malformations
- Developmental delay
- Occulomotor apraxia
CEP164-related disorders fall into the ciliopathy spectrum slaats2015:
| Disorder |
CEP164 Role |
Phenotype |
| NPHP |
Causative |
Kidney cysts, fibrosis |
| Senior-Loken |
Causative |
NPHP + retinal degeneration |
| Joubert |
Associated |
Cerebellar malformation |
| Meckel syndrome |
Possible |
Encephalocele, polydactyly |
CEP164 shows broad expression:
- Kidney: Tubular epithelial cells (highest)
- Retina: Photoreceptor cells
- Brain: Cortex, cerebellum, hippocampus
- Lung: Respiratory epithelium
- Testis: Spermatogenic cells
- Various epithelia: Throughout the body
Within the nervous system braun2015:
- Cerebral cortex: Pyramidal neurons
- Hippocampus: Dentate gyrus, CA regions
- Cerebellum: Purkinje cells
- Subventricular zone: Neural stem cells
- Olfactory bulb: Sensory neurons
- Neurons: Expression in excitatory and inhibitory neurons
- Astrocytes: Moderate expression
- Oligodendrocytes: Lower expression
- Neural progenitors: High expression during development
- Microglia: Minimal expression
Modulating CEP164 and ciliary pathways represents a therapeutic strategy ibanez-tallon2019:
- Small molecules: Promote ciliogenesis
- Gene therapy: Deliver functional CEP164
- Protein replacement: Recombinant protein delivery
- Hedgehog modulators: Smoothened agonists/antagonists
- Wnt pathway: Beta-catenin modulators
- Cyclic AMP: ciliary signaling regulation
- Restore ciliary function: Enhance CEP164 activity
- Protect centrosome: Prevent centrosome stress
- Enhance DNA repair: Support genomic integrity
- Modulate signaling: Normalize ciliary pathways
| Challenge |
Approach |
| BBB penetration |
Target CNS-penetrant molecules |
| Protein delivery |
Viral vectors for gene therapy |
| Specificity |
Target ciliary-specific pathways |
| Timing |
Early intervention in disease |
- Ciliary modulators in clinical trials for other conditions
- Gene therapy approaches for inherited ciliopathies
- Small molecule enhancers of ciliary signaling
- Cep164 knockout mice: Embryonic lethal
- Conditional knockouts: Tissue-specific phenotypes
- Zebrafish models: Ciliary dysfunction phenotypes
- NPHP mouse models with Cep164 mutations
- Ciliary dysfunction models for neurodegeneration
- Centrosome ablation studies
- Ciliary-specific functions: How CEP164 differs from other centriolar proteins
- Neuronal roles: Specific functions in neurons vs. other cell types
- Therapeutic targeting: How to specifically modulate CEP164
- Cryo-EM studies: CEP164 structure at atomic resolution
- Single-cell analysis: CEP164 in specific neuronal populations
- Ciliary organoids: Brain organoid models
- Proteomics: CEP164 interaction networks