The PLXNA3 Puzzle: A Genetic Key to Understanding MS Severity

Multiple sclerosis (MS) is a disease full of paradoxes. One of the most persistent is its relationship with sex: women are far more likely to develop MS, yet men tend to experience a faster, more aggressive progression. Clinicians have known this for decades, but why this happens has remained largely unexplained.

A study by Qureshi and colleagues now adds a compelling piece to the puzzle. Using exome sequencing in Kuwaiti MS patients, the researchers identified a genetic variant—rs5945430 in the PLXNA3 gene—that appears to specifically worsen MS severity in men. Even more intriguingly, the study suggests that estradiol, a sex hormone usually higher in women, may help shield females from the harmful effects of this variant.

This is one of the first concrete genetic leads that may explain sex-specific differences in MS progression.

Understanding the Players: MS, Sex Differences, and PLXNA3
MS and its sex imbalance MS is caused by an immune-driven attack on the central nervous system, leading to demyelination and progressive neurodegeneration. Women develop MS at roughly twice the rate of men, but men who do develop MS tend to accumulate disability more quickly.

Many hypotheses have been proposed—immunology, hormones, lifestyle, epigenetics—but the field has struggled to uncover genetic variants that explain this male vulnerability.

What is PLXNA3?
PLXNA3 encodes Plexin A3, a receptor involved in:

axon guidance

synaptic remodeling

oligodendrocyte migration

immune regulation

These functions place the gene at the intersection of neurodevelopment, repair, and inflammation—all highly relevant to MS pathology.

A Clever Study Design to Probe Sex Differences
The team recruited 213 Kuwaiti MS patients and used a clever comparative approach:

They sequenced the exomes of 8 men with severe MS and 18 women with milder disease but similar disease duration.

This allowed them to look specifically for mutations enriched in men with worse progression.

From thousands of variants, one stood out: rs5945430, a missense mutation (D863E) in PLXNA3 located on the X chromosome.

Because men have only one X chromosome, any harmful variant there is fully expressed, whereas women may buffer its effects through random X-inactivation.

The Key Finding: The G Variant of rs5945430 Worsens MS in Men
In a larger cohort of 187 MS patients, the authors confirmed their discovery:

Men with the G allele had significantly higher disability (EDSS) and worse MS severity scores (MSSS)

p = 0.013, OR 3.8—a nearly fourfold increased risk of severe disease.

Women showed no significant association between the variant and disease severity.

This makes rs5945430 a male-specific disease-modifying variant.

Why the Sex Difference? Estradiol May Hold the Answer
The researchers explored hormonal influences, focusing on estradiol, which previous studies suggested can down-regulate PLXNA3 expression.

Their findings:

MS males had significantly lower estradiol levels than healthy men (p < 0.001).

Men with the G allele tended toward even lower estradiol levels.

Women with MS had estradiol levels similar to healthy women, potentially buffering against PLXNA3 overexpression.

The proposed mechanism:

Low estradiol → higher PLXNA3 expression → dysfunctional Plexin A3 signaling → impaired remyelination and increased neurodegeneration, particularly in men.

This matches what is known about semaphorin–plexin signaling: dysregulation can hinder oligodendrocyte migration and remyelination—key processes in MS recovery.

What Could Dysfunctional PLXNA3 Do in MS?
The variant changes an amino acid in an immunoglobulin-like domain important for interacting with semaphorins (SEMA3A, SEMA3F).

Possible consequences:

altered receptor folding or stability

diminished or exaggerated binding to guidance cues

disrupted repair pathways

excessive axon pruning

poor remyelination

These processes could drive the faster disability accumulation seen in men.

Why This Study Matters
1. A rare example of a sex-specific MS genetic modifier

Most MS genetics research focuses on disease risk, not disease severity, and almost none identifies sex-specific effects.

2. Offers a biological hypothesis explaining male vulnerability

Low estradiol + an X-linked risk variant = higher functional impact in men.

3. Potential for personalized medicine

If validated, rs5945430 could eventually guide:

early aggressive treatment in genetically susceptible men

hormone-based adjunct therapies

stratification in clinical trials

4. A model for studying sex differences in other neuroimmune diseases

Limitations to Keep in Mind
The authors acknowledge several caveats:

modest sample size for men (a common challenge in MS research)

cross-sectional design—cannot track estradiol and disability changes over time

findings still need replication in other ethnic groups

functional experiments to confirm mechanistic effects were not performed

Still, the discovery is biologically plausible and aligns with known pathways in MS.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Qureshi, M., Hatem, M., Alroughani, R. et al. PLXNA3 Variant rs5945430 is Associated with Severe Clinical Course in Male Multiple Sclerosis Patients. Neuromol Med 19, 286–292 (2017). https://doi.org/10.1007/s12017-017-8443-0