SLC45A4 is a pain gene encoding a neuronal polyamine transporter

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Conflicts of Interest

Identified Weaknesses

Rating Explanation

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Paper Summary

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A New Pain Gene Found (In Mice, But Still Cool!)

This study used human genetic data and mouse models to identify SLC45A4, a gene encoding a polyamine transporter, as being associated with chronic pain intensity, particularly for heat and tonic pain. Mice lacking this gene had reduced sensitivity to these types of pain, alongside changes in polyamine levels. The study also found changes in GABA levels in the spinal cord of knockout mice.

Possible Conflicts of Interest

J.E.L. is an employee of AstraZeneca. D.L.B. received consulting fees from various pharmaceutical companies. The PAINSTORM consortium received funding from Eli Lilly and AstraZeneca. The DOLORisk consortium received funding from Eli Lilly. H.R.K. has financial ties to several pharmaceutical companies, including advisory board positions, consulting fees, research funding, and is listed as an inventor on a patent related to buprenorphine treatment response.

Identified Weaknesses

Reliance on Mouse Models

The study heavily relies on mouse models, and while there are similarities between mouse and human pain systems, there are also significant differences. This makes it difficult to directly translate the findings to human pain experiences.

Lack of Mechanistic Explanation

The study found an association between SLC45A4 and chronic pain intensity, but it doesn't explain *how* variations in this gene cause differences in pain perception. More research is needed to understand the underlying mechanism.

Small Effect Sizes of Genetic Variants

The common genetic variants linked to pain have small effect sizes, which can be hard to detect in functional assays.

Unclear Role of N718D Variant

The study did not fully elucidate the role of the N718D variant identified in the GWAS, as their functional assays did not reveal a change in transport activity.

Rating Explanation

This study presents strong evidence for SLC45A4's role in pain perception, combining human genetic data with mechanistic studies in mice. The multi-faceted approach, including GWAS, cell assays, structural biology, and behavioral experiments strengthens the findings. However, the reliance on mouse models and the lack of a full mechanistic understanding limit the rating to a 4.

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