CRB2 mutation causes autosomal recessive retinitis pigmentosa

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Retinitis pigmentosa (RP) is a leading cause of inherited blindness with significant genetic heterogeneity.
• Mutations in CRB1 are known to cause RP, but the role of CRB2 has been hypothesized but unconfirmed.

Purpose of the Study:

• To identify novel genes causing RP in a Chinese consanguineous family.
• To investigate the pathogenic mechanisms of CRB2 mutations in RP.

Main Methods:

• Whole Exome Sequencing (WES) to identify genetic mutations.
• In vitro cellular studies to analyze the functional impact of the identified mutation.
• Ophthalmic and systemic evaluations of affected patients.

Main Results:

• A homozygous missense mutation (CRB2 p.R1249G) was identified and segregated with the RP phenotype in the family.
• The mutation destabilized CRB2 mRNA and protein, reducing expression.
• The mutation induced epithelial-mesenchymal transition (EMT) in retinal pigment epithelium (RPE) cells, leading to RPE dysfunction, degeneration, and apoptosis.

Conclusions:

• CRB2 is a novel causative gene for non-syndromic RP.
• The CRB2 p.R1249G mutation causes RP by promoting RPE cell EMT, dysfunction, and loss.
• This study highlights the role of RPE EMT in RP pathogenesis and provides insights into CRB2-related retinopathy.