Biallelic BAIAP3 Variants Are Associated with Isolated Retinitis Pigmentosa

Area of Science:

• Genetics
• Ophthalmology
• Cell Biology

Background:

• Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies causing photoreceptor cell loss.
• Genetic mutations affecting the photoreceptor connecting cilium are implicated in approximately one-third of retinal degeneration cases.
• The genetic basis for many RP cases remains undiagnosed.

Purpose of the Study:

• To investigate the genetic cause of undiagnosed degenerative retinopathy in a patient.
• To identify novel genes associated with isolated retinitis pigmentosa.
• To elucidate the functional consequences of identified genetic variants on photoreceptor function and signaling pathways.

Main Methods:

• Whole genome sequencing was performed to identify the genetic basis of the patient's condition.
• Functional studies included confocal microscopy of patient-derived fibroblasts and BAIAP3-depleted cells to analyze cilia structure.
• Real-time PCR was used to assess mRNA levels of GLI1, a marker of Sonic hedgehog signaling.

Main Results:

• Compound heterozygosity for two missense variants in the BAIAP3 gene was identified.
• BAIAP3 variants led to elongated cilia in patient-derived and BAIAP3-depleted fibroblasts.
• Reduced GLI1 mRNA levels indicated Sonic hedgehog signaling pathway dysregulation in patient cells.

Conclusions:

• Biallelic loss-of-function variants in BAIAP3 are implicated as a cause of isolated retinitis pigmentosa.
• BAIAP3 plays a crucial role in photoreceptor function, potentially through its involvement in trafficking and ciliogenesis.
• These findings expand the genetic landscape of RP and highlight BAIAP3 as a potential therapeutic target.