CEP290

Cilia effects upon perturbation of CEP290

Cilia number / % ciliated:

Decreased cilia number

Loss-of-function effect:

Longer cilia

Ciliogenesis screen results (2 screens)

• Wheway et al. 2015 (siRNA) [siRNA]: Ciliogenesis Defect (z=-6.53) PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: Increased Signaling (Negative Regulator) PMID:29459680

Phenotypes

Mouse phenotype:

preweaning lethality, incomplete penetrance, hemorrhage, no spontaneous movement, abnormal placenta morphology, decreased mean corpuscular hemoglobin concentration, abnormal blood vessel morphology, decreased mean corpuscular hemoglobin

Mouse ciliopathy phenotype:

abnormal facial morphology, abnormal head shape

Human ciliopathy phenotype:

Joubert syndrome 5; Senior-Loken syndrome 6; Leber congenital amaurosis 10; Meckel syndrome, type 4; Bardet-Biedl syndrome 14; CEP290-related ciliopathy; Meckel syndrome; Leber congenital amaurosis; Joubert syndrome; Senior-Loken syndrome; Joubert syndrome with oculorenal defect; nephronophthisis; Nephronophthisis; retinitis pigmentosa; Joubert syndrome 1; Bardet-Biedl syndrome 1

Ciliopathy associations

• Bardet-Biedl Syndrome
• COACH Syndrome
• Joubert Syndrome
• Leber Congenital Amaurosis
• Meckel-Gruber Syndrome
• Nephronophthisis
• Senior-Løken Syndrome

Subcellular localization

basal body, centrosome, cytosol, nucleus, transition zone

Functional category

• Ciliary assembly/disassembly
• Trafficking (BBSome, small GTPases, vesicular transport, ATPases)
• Actin & cytoskeleton regulation
• Protein processing & maturation
• Signaling (Hedgehog, GPCRs, ion channels)
• Ciliary membrane
• Transition zone

Function

Assembly and stabilisation of the primary cilium as well as centrosomal function (30478281, 22563985). Interacts with a centriolar satellite protein PCM-1 and is implicated in molecular pathways related to BBS4 function. CEP250 binds PCM- 1 and are involved in ciliary targeting of Rab8 required to promote ciliogenesis. Interacts with components of both dynein and kinesin motor machineries (18772192). Regulation of intracellular protein trafficking by association with microtubule-based transport protein RPGR (16632484). CEP250 plays an important role in the formation and stabilisation of the primary cilium as well as centrosomal function, stabilises the linkage of axoneme to the ciliary membrane to maintain the integrity of the ciliary diffusion barrier. CEP290 is critical for positioning the molecular components that are necessary for correct processing of Shh sig lling in the primary cilium (30478281). Next, RNA-seq analysis was performed to explore which signals and molecules are important for the formation of dilated pronephric tubule observed in the xCEP290 morphant kidney. The hallmark gene set associated with the IL-6/JAK/STAT3 signaling pathway was upregulated in xCEP290 morphant kidney, and inhibition of this signaling by JAK inhibitor ruxolitinib suppressed the dilated pronephric tubule in xCEP290 morphants. Furthermore, the expression level of transcription factor Xenopus FOSL1 (xFOSL1), whose gene expression is regulated by IL-6 signaling, was upregulated in xCEP290 morphant kidney, and overexpression of xFOSL1 induced pronephric tubular dilation. These results together revealed that abnormal activation of IL-6/JAK/STAT3/FOSL1 signal axis is responsible for dilated pronephric tubule resembling cystic lesions observed in polycystic kidney disease of JSRD patients with CEP290 gene mutations. (40570958).

Model organism evidence