Founder Homozygous Nonsense CREB3 Variant and Variable-Onset Retinal Degeneration

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Identifying the genetic underpinnings of inherited retinal diseases (IRDs) is crucial for accurate diagnosis and developing targeted therapies.
• The role of the CREB3 gene in retinal function and its potential link to IRDs were previously unexplored.

Purpose of the Study:

• To investigate the association between a homozygous nonsense variant in the CREB3 gene and the development of IRDs.
• To analyze the clinical and genetic characteristics of patients with this specific CREB3 variant.

Main Methods:

• Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were performed on 13 patients diagnosed with retinitis pigmentosa or cone-rod degeneration.
• Expression analysis using reverse transcription-polymerase chain reaction and Western blot was conducted on patient-derived fibroblasts.
• Immunohistochemistry staining on mouse retinal sections was used to determine CREB3 protein localization.

Main Results:

• A founder homozygous nonsense variant in CREB3 (c.881G>A, p.Trp294*) was identified in 13 patients from four unrelated families, primarily of North-African Jewish and Italian descent.
• Patients exhibited retinal degeneration with variable onset and clinical presentations, including rod-cone and cone-rod dystrophies.
• The variant resulted in a truncated CREB3 protein, and CREB3 expression was detected in various retinal cell types, highlighting its importance in photoreceptor function.

Conclusions:

• This study establishes a significant association between a CREB3 nonsense variant and IRDs.
• The findings suggest CREB3 plays a vital role in retinal health, and its dysfunction can lead to retinal degeneration.
• The previously observed upregulation of CREB3 following UV radiation may contribute to the clinical variability seen in affected individuals.