Loss of CEP162 function at the primary cilium delays ciliogenesis and causes retinal ciliopathy in humans

Nuzhat, N.; Van Schil, K.; Liakopoulos, S.; Bauwens, M.; Duenas Rey, A.; Käseberg, S.; Jäger, M.; Willer, J. R.; Winter, J.; Truong, H.; Gruartmoner, N.; Van Heetvelde, M.; Wolf, J.; Merget, R.; Grasshoff-Derr, S.; Van Dorpe, J.; Hoorens, A.; Stöhr, H.; Mansard, L.; Roux, A.-F.; Langmann, T.; Dannhausen, K.; Rosenkranz, D.; Wissing, K. M.; Van Lint, M.; Rossmann, H.; Häuser, F.; Nürnberg, P.; Thiele, H.; Zechner, U.; Pearring, J. N.; De Baere, E.; Bolz, H. J.

doi:10.1101/2021.11.23.469779

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bioRxiv · 10.1101/2021.11.23.469779

Loss of CEP162 function at the primary cilium delays ciliogenesis and causes retinal ciliopathy in humans

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Abstract

Defects in primary or motile cilia result in a variety of human pathologies, and retinal degeneration is frequently associated with these so-called ciliopathies. We show that homozygosity for a truncating variant in CEP162, a centrosome and microtubule-associated protein required for transition zone (TZ) assembly during ciliogenesis and neuronal differentiation in the retina, causes late-onset retinitis pigmentosa in 2 unrelated families. The mutant CEP162-E646R*5 protein is expressed and properly localized to the mitotic spindle but missing from the basal body in primary and photoreceptor cilia. This impairs recruitment of TZ components to the basal body and corresponds to complete loss of CEP162 function at the ciliary compartment, reflected by delayed formation of dysmorphic cilia. In contrast, rescue of increased cell death in the developing mouse retina after shRNA knockdown of Cep162 by expression of CEP162-E646R*5 indicates that the mutant retains its role for retinal neurogenesis. Human retinal degeneration thus results from specific loss of ciliary CEP162 function. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=134 HEIGHT=200 SRC="FIGDIR/small/469779v3_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@593dccorg.highwire.dtl.DTLVardef@e84d7forg.highwire.dtl.DTLVardef@137ce56org.highwire.dtl.DTLVardef@cba1f7_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Nuzhat, N., Van Schil, K., Liakopoulos, S., Bauwens, M., Duenas Rey, A., Käseberg, S., Jäger, M., Willer, J. R., Winter, J., Truong, H., Gruartmoner, N., Van Heetvelde, M., Wolf, J., Merget, R., Grasshoff-Derr, S., Van Dorpe, J., Hoorens, A., Stöhr, H., Mansard, L., Roux, A.-F., Langmann, T., Dannhausen, K., Rosenkranz, D., Wissing, K. M., Van Lint, M., Rossmann, H., Häuser, F., Nürnberg, P., Thiele, H., Zechner, U., Pearring, J. N., De Baere, E., Bolz, H. J.. 2021-11-23. Loss of CEP162 function at the primary cilium delays ciliogenesis and causes retinal ciliopathy in humans. https://doi.org/10.1101/2021.11.23.469779

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