Pathogenicity Analysis of Two Novel CRB1 Mutations in Three Chinese Inherited Retinal Dystrophy Families and a Literature Review.

PURPOSE: This study aims to analyze the clinical features of three inherited retinal dystrophies (IRDs) pedigrees with CRB1 mutations, and assess pathogenicity of novel variants.

METHODS

A retrospective clinical study was conducted, involving three IRD pedigrees. Whole exome sequencing was performed. The in silico molecular genetic analysis and bioinformatics analysis were conducted. Western blot and cycloheximide chase experiments were used for protein expression and stability. We also conducted a literature review to analyze diagnosis and mutation distribution characteristics of reported Chinese patients with CRB1-IRD.

RESULTS

Three probands, including two cone-rod dystrophy (CORD) and one retinitis pigmentosa (RP), carried compound heterozygous CRB1 variants. Six variants were identified, including two novel variants (c.1122C>G: p.S374R and c.2233A>G: p.T745A). In vitro, the expression levels of CRB1 with S374R variant significantly reduced. The S374R, G1288S, and T745A showed accelerated protein degradation rates and reduced protein stability. Literature review revealed 3 high-frequency mutation regions and 13 high-frequency mutation sites in the Chinese CRB1-IRD population, with approximately 95% of patients diagnosed with Leber congenital amaurosis (LCA) or RP.

CONCLUSIONS

This study identified two novel CRB1 mutations that reduced CRB1 expression by impairing protein stability. In literature review, we identified 3 mutation hotspots and 13 recurrent mutations in Chinese patients with CRB1-IRD.

TRANSLATIONAL RELEVANCE: We identified two novel CRB1 variants impairing protein stability. Combined with mutation hotspots identified in Chinese patients, enhancing genetic screening accuracy and expanding ethnic-specific mutation databases.