Ramp Sequence May Explain Synonymous Variant Association with Alzheimer's Disease in the Paired Immunoglobulin-like
Justin B Miller1,2,3,4, J Anthony Brandon2, Lauren M Harmon5
1Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40506, USA.
Biomedicines
|March 28, 2025
Summary
The rs2405442:T>C variant in the PILRA gene significantly reduces both mRNA and protein levels. This finding suggests that codon ramp sequences may regulate Alzheimer's disease-associated genes.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- A synonymous variant, rs2405442:T>C, in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) gene has been linked to a reduced risk of Alzheimer's disease (AD).
- The precise biological mechanism underlying this association remains largely unelucidated.
Purpose of the Study:
- To investigate the hypothesis that the rs2405442:T>C variant diminishes PILRA mRNA and protein expression.
- To explore the role of codon ramp sequences in regulating gene expression relevant to AD.
Main Methods:
- Quantitative polymerase chain reactions (qPCRs) were employed to assess mRNA levels.
- Enzyme-linked immunosorbent assays (ELISAs) were utilized to measure protein levels.
- Experiments were conducted using Chinese hamster ovary (CHO) cells to evaluate the variant's effects.
Main Results:
- The rs2405442:T>C variant led to a statistically significant decrease in both PILRA mRNA levels (p = 1.9184 × 10⁻¹³) and protein levels (p = 0.01296) compared to the wildtype.
- These observed decreases align with the predicted impact of the variant on a codon ramp sequence at the 5' end of PILRA.
Conclusions:
- The study demonstrates that the rs2405442:T>C variant directly influences PILRA mRNA and protein expression.
- The findings suggest that codon ramp sequences could be a regulatory mechanism for Alzheimer's disease-associated genes, independent of protein product modification.
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