DNA Variant in the RPGRIP1L Gene Influences Alternative Splicing.

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• The RPGRIP1L gene encodes a ciliary protein crucial for brain development, left-right asymmetry, and signaling pathways.
• RPGRIP1L variants are linked to retinal degeneration, Joubert syndrome, and Meckel syndrome, all involving primary ciliary dysfunction.
• Genetic studies suggest RPGRIP1L involvement in psychiatric disorders like bipolar disorder and autism.

Purpose of the Study:

• To identify common variants in RPGRIP1L that affect gene function.
• To investigate the impact of identified variants on alternative splicing in the brain.

Main Methods:

• Identification of a common variant, rs7203525, in the RPGRIP1L gene.
• Analysis of alternative splicing in human postmortem brain tissue.
• In vitro validation using minigene assays and mutagenesis.

Main Results:

• The common variant rs7203525 was found to influence alternative splicing, increasing exon 20 inclusion in RPGRIP1L.
• This alternative splicing event was confirmed in human brain tissue and validated experimentally.
• The predominant RPGRIP1L isoform in adult brains lacks exon 20, suggesting this variant-induced inclusion may alter brain function.

Conclusions:

• A common RPGRIP1L variant (rs7203525) directly impacts alternative splicing, potentially affecting brain function.
• This splicing alteration provides a novel mechanism linking RPGRIP1L to neurological and psychiatric disorders.
• Further research is warranted to explore the functional consequences of this splicing change in brain development and disease.