VPS13B

Cilia effects upon perturbation of VPS13B

Loss-of-function effect:

Longer cilia

Ciliogenesis screen results (3 screens)

• Wheway et al. 2015 (siRNA) [siRNA]: No effect PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: No Significant Effect PMID:29459680
• Elliott et al. 2025 (CRISPRa) [CRISPRa]: Disassembly Trigger (casTLE Effect=-2.67) PMID:41160700

Phenotypes

Mouse phenotype:

spermatogenesis defect, vacuolation, dysplasia, aspermia, decreased lymphocyte cell number, hydropic degeneration, decreased circulating alkaline phosphatase level, abnormal eye morphology, decreased exploration in new environment, decreased lean body mass, steatosis, increased startle reflex, impaired glucose tolerance, decreased leukocyte cell number, abnormal skin morphology, increased total body fat amount, decreased body length, germ cell defect, increased grip strength, small heart, lens extrusion, small spleen, increased mean corpuscular volume, enlarged lymph nodes

Mouse ciliopathy phenotype:

cataract, abnormal lens morphology, male infertility, cataract, abnormal liver morphology

Human ciliopathy phenotype:

Intellectual disability

Subcellular localization

cilia associated gene, nucleus

Function

We speculated that VPS13B mutations may indirectly affect cilia by altering the lipid and protein composition of cilia, leading to some of the distinctive phenotypes in CS. To test this, I treated cultured cells with VPS13B siRNAs and analyzed cilia structure and composition. Apart from observing a wide range of cellular defects including mTORC1 downregulation, increased autophagy, G0 arrest and lysosomal structural defects, I also observed a variety of defects at the levels of the primary cilium. These include reduced levels of the lipid PI(4,5)P2 at the ciliary base, longer cilia and inability to activate the Hedgehog signaling pathway. These results suggest that VPS13B indirectly regulates ciliary membrane composition and function. I also analyzed skin fibroblasts from CS patients and compared them with those of healthy controls. Interestingly, despite lacking the full length protein, patients still show a robust signal corresponding to VPS13B at the Golgi complex, suggesting that they might express alternative isoforms that still can localize to this organelle. However, CS cilia were very similar to controls. Curiously, treatment of CS fibroblasts with VPS13B siRNAs gives rise to a plethora of ciliary defects including Hedgehog inactivation. This supports the existence of shorter, at least partially functional VPS13B isoforms in CS patients. To understand if this situation was general or specific to the skin, I decided to investigate disease-relevant tissues. I derived neural rosettes from induced pluripotent stem cells of a healthy control and a CS patient. Interestingly, neural progenitor cells (NPCs) from CS rosettes presented also longer and abnormal cilia compared to control NPCs, suggesting the occurrence of a ciliary impairment in brain-related tissues. (https://diposit.ub.edu/dspace/handle/2445/199343)