Ramp Sequence May Explain Synonymous Variant Association with Alzheimer’s Disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA)

Ramp Sequence May Explain Synonymous Variant Association with Alzheimer’s Disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA)

<b>Background:</b> The synonymous variant <i>NC_000007.14:g.100373690T>C</i> (<i>rs2405442:T>C</i>) in the Paired Immunoglobulin-like Type 2 Receptor Alpha (<i>PILRA</i>) gene was previously associated with decreased risk for Alzheimer’s disease...

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Main Authors: Justin B. Miller, J. Anthony Brandon, Lauren M. Harmon, Hady W. Sabra, Chloe C. Lucido, Josue D. Gonzalez Murcia, Kayla A. Nations, Samuel H. Payne, Mark T. W. Ebbert, John S. K. Kauwe, Perry G. Ridge
Format: Article
Language:English
Published: MDPI AG 2025-03-01
Series:Biomedicines
Subjects:
Alzheimer’s disease
ramp sequence
genetic association
codon usage bias
disease association
Online Access:https://www.mdpi.com/2227-9059/13/3/739
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Summary:<b>Background:</b> The synonymous variant <i>NC_000007.14:g.100373690T>C</i> (<i>rs2405442:T>C</i>) in the Paired Immunoglobulin-like Type 2 Receptor Alpha (<i>PILRA</i>) gene was previously associated with decreased risk for Alzheimer’s disease (AD) in genome-wide association studies, but its biological impact is largely unknown. <b>Objective:</b> We hypothesized that <i>rs2405442:T>C</i> decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the 5′ end of <i>PILRA</i>. <b>Methods:</b> We assessed <i>rs2405442:T>C</i> predicted effects on <i>PILRA</i> through quantitative polymerase chain reactions (qPCRs) and enzyme-linked immunosorbent assays (ELISAs) using Chinese hamster ovary (CHO) cells. RESULTS: Both mRNA (<i>p</i> = 1.9184 × 10<sup>−13</sup>) and protein (<i>p</i> = 0.01296) levels significantly decreased in the mutant versus the wildtype in the direction that we predicted based on the destruction of a ramp sequence. <b>Conclusions:</b> We show that <i>rs2405442:T>C</i> alone directly impacts <i>PILRA</i> mRNA and protein expression, and ramp sequences may play a role in regulating AD-associated genes without modifying the protein product.
ISSN:2227-9059

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