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CEP162 deficiency causes human retinal degeneration and reveals a dual role in ciliogenesis and neurogenesis
Nafisa Nuzhat1, Kristof Van Schil2,3, Sandra Liakopoulos4,5
1Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
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.
Insights
Genetic defects in cilia cause human diseases. A mutation in CEP162, a protein crucial for cilia formation, caused retinitis pigmentosa in two families due to loss of its ciliary function.
Area of Science:
- Genetics
- Cell Biology
- Ophthalmology
Background:
- Cilia are essential cellular structures involved in various biological processes.
- Defects in cilia, known as ciliopathies, are linked to numerous human diseases, including retinal degeneration.
- CEP162 is a protein vital for cilia assembly and neuronal development.
Purpose of the Study:
- To investigate the role of CEP162 in retinal degeneration.
- To identify the genetic cause of late-onset retinitis pigmentosa in two families.
Main Methods:
- Genetic analysis of affected individuals.
- Protein expression and localization studies.
- Cellular assays using knockdown and mutant protein expression in mouse retina models.
Main Results:
- A truncating variant in CEP162 (CEP162-E646R*5) was identified as the cause of retinitis pigmentosa in two families.
- The mutant CEP162 protein localized correctly to the mitotic spindle but not the basal body of cilia.
- This defect impaired transition zone assembly, leading to abnormal cilia formation and loss of CEP162's ciliary function.
- CEP162 knockdown in mouse retinas increased cell death, but the mutant protein could partially rescue this, suggesting retained neurogenesis function.
Conclusions:
- Late-onset retinitis pigmentosa in these families resulted from a specific loss of CEP162's function within the ciliary compartment.
- CEP162 plays a critical role in maintaining photoreceptor health through its function in cilia assembly.
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