VHL

Cilia effects upon perturbation of VHL

Cilia number / % ciliated:

Decreased cilia number

Loss-of-function effect:

Shorter cilia

Overexpression effect:

No effect

Ciliogenesis screen results (5 screens)

• Kim2016: Not Reported
• Wheway et al. 2015 (siRNA) [siRNA]: Ciliogenesis Defect (z=-3.68) PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: No Significant Effect PMID:29459680
• Roosing et al. 2015 (siRNA) [siRNA]: No effect PMID:26595381
• Elliott et al. 2025 (CRISPRa) [CRISPRa]: Disassembly Trigger (casTLE Effect=-2.51) PMID:41160700

Phenotypes

Human ciliopathy phenotype:

von Hippel-Lindau Disease: heterozygous VHL mutations predispose to clear-cell renal cell carcinoma (ccRCC), CNS and retinal hemangioblastomas, pheochromocytomas, endolymphatic-sac tumours, and renal/pancreatic cysts. ccRCC is the most common renal malignancy. Cilia-loss in VHL-/- cells precedes/contributes to cyst formation and tumourigenesis.

Ciliopathy associations

• Renal Cell Carcinoma

References: PMID:17912253

Subcellular localization

axoneme, basal body, cilia, ciliary tip

References: PMID:17912253, PMID:41005307, PMID:17450132

Functional category

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

Function

VHL encodes the von Hippel-Lindau tumour suppressor protein. Heterozygous germline mutations cause von Hippel-Lindau disease (OMIM #193300), characterised by predisposition to clear-cell renal cell carcinoma (ccRCC), pheochromocytomas, hemangioblastomas of the CNS and retina, and renal cysts. Cilia mechanism: Lolkema et al. 2008 (Eur J Hum Genet, PMID 17912253) demonstrated that VHL-/- ccRCC cells lose primary cilia and ciliary mechanotransduction, with rapid restoration of cilia assembly upon reintroduction of wild-type VHL but NOT disease-associated variant alleles. Reduction of cellular VHL levels causes a corresponding decrease in ciliated cells, indicating a role for VHL in both cilia initiation and maintenance. VHL-/- renal cysts in VHL-disease patients are postulated precursor lesions for ccRCC. The cilium-loss → cystogenesis → tumourigenesis axis positions VHL ccRCC within the ciliopathy spectrum, parallel to PKD where polycystin loss disrupts ciliary signalling.