CEP162 deficiency causes human retinal degeneration and reveals a dual role in ciliogenesis and neurogenesis

Nafisa Nuzhat, Kristof Van Schil, Sandra Liakopoulos, Miriam Bauwens, Alfredo Dueñas Rey, Stephan Käseberg, Melanie Jäger, Jason R Willer, Jennifer Winter, Hanh M Truong, Nuria Gruartmoner, Mattias Van Heetvelde, Joachim C Wolf, Robert Merget, Sabine Grasshoff-Derr, Jo Van Dorpe, Anne Hoorens, Heidi Stöhr, Luke Mansard, Anne-Françoise RouxThomas Langmann, Katharina Dannhausen, David Rosenkranz, Karl M Wissing, Michel Van Lint, Heidi Rossmann, Friederike Häuser, Peter Nürnberg, Holger Thiele, Ulrich Zechner, Jillian N Pearring, Elfride De Baere, Hanno J Bolz

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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 found that homozygosity for a truncating variant in CEP162, a centrosome and microtubule-associated protein required for transition zone assembly during ciliogenesis and neuronal differentiation in the retina, caused late-onset retinitis pigmentosa in 2 unrelated families. The mutant CEP162-E646R*5 protein was expressed and properly localized to the mitotic spindle, but it was missing from the basal body in primary and photoreceptor cilia. This impaired recruitment of transition zone components to the basal body and corresponded to complete loss of CEP162 function at the ciliary compartment, reflected by delayed formation of dysmorphic cilia. In contrast, shRNA knockdown of Cep162 in the developing mouse retina increased cell death, which was rescued by expression of CEP162-E646R*5, indicating that the mutant retains its role for retinal neurogenesis. Human retinal degeneration thus resulted from specific loss of the ciliary function of CEP162.

Original languageEnglish
Article numbere161156
Number of pages13
JournalJournal of Clinical Investigation
Volume133
Issue number8
Early online date2023
DOIs
Publication statusPublished - 17 Apr 2023

Bibliographical note

Copyright:
This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine

Keywords

  • Cell Biology
  • Genetic diseases
  • Genetics
  • Molecular genetics
  • Retinopathy

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