A Founder Homozygous Nonsense Variant in CREB3 Causes a Variable Retinal Degeneration Phenotype

Purpose:
To report CREB3 as a novel genetic basis of inherited retinal diseases (IRDs) in families mostly of North African Jewish origin.
Methods:
Thirteen patients with a clinical diagnosis of retinitis pigmentosa or macular degeneration were analyzed using next-generation sequencing (NGS). Homozygosity mapping was performed on the Franklin platform for seven patients from four unrelated families. Expression analysis was performed on patient-derived skin fibroblasts using the reverse transcription–polymerase chain reaction (RT-PCR) and Western blot analysis, as well as by interrogating previously published retinal single-cell RNA-seq data. Immunohistochemistry staining (IHC) was performed on wild-type mouse retinal sections using an anti-CREB3 antibody.
Results:
A founder homozygous nonsense variant in CREB3 (c.881G>A, p.Trp294*) was identified in thirteen patients from four unrelated families. All patients manifested retinal degeneration with varying levels of severity. Homozygosity mapping revealed that out of the seven patients, six patients of North African Jewish descent had an identical haplotype. In patient-derived fibroblasts, the mutant mRNA transcript generated a truncated CREB3 protein. Expression analysis and IHC revealed CREB3 RNA and protein expression in various retinal cell types, indicating its vital role in photoreceptor function.
Conclusion:
We report here for the first time the involvement of CREB3 in IRDs. CREB3 was previously shown to be upregulated following UV radiation, which might contribute to extensive clinical variability observed in this relatively large cohort of homozygous patients for the same truncating variant.