How a Single Gene Variant May Accelerate Multiple Sclerosis: The DYSF-ZNF638 Connection

Multiple sclerosis (MS) is a complex immune-mediated disease that attacks the brain and spinal cord. While most people with MS experience relapsing symptoms that can stabilize or even improve with treatment, others face a much more aggressive progression — losing neurological function faster and more permanently.

For decades, scientists have wondered: Why do some people’s MS worsen so much more rapidly than others’? The answer, at least partly, might lie in their DNA.

A Gene Variant Linked to MS Severity
Recent genome-wide studies identified a genetic variant called rs10191329, located between two genes — DYSF (DYSFerlin) and ZNF638 (zinc finger protein 638) — as a possible driver of MS progression. People who carry two copies of the “A” version (rs10191329AA) tend to reach severe disability milestones years earlier than others.

In the new study by Hendrik J. Engelenburg and colleagues at the Netherlands Institute for Neuroscience and Erasmus MC, researchers took a deep dive into the biology of this variant. Using post-mortem brain tissue from the Netherlands Brain Bank, they compared six MS donors carrying rs10191329AA with twelve matched controls (rs10191329CC) to uncover how this genetic difference might reshape the brain’s pathology.

Inside the Brains: What the Team Found
1. More “Foamy” Microglia — Signs of Chronic Inflammation
Under the microscope, lesions from rs10191329AA carriers were packed with foamy microglia — immune cells engorged with myelin debris. These cells, although vital for clearing damage, can turn harmful when overactivated.

The team found over twice as many foamy myeloid cells in these patients’ lesions compared to controls, indicating a more inflammatory and destructive environment.

2. Evidence of Neuronal Stress and Loss
Markers of acute axonal stress — like amyloid precursor protein (APP) accumulations — were significantly higher in rs10191329AA brains. Moreover, neuronal density in cortical layer 2 was notably reduced, signaling direct neurodegeneration. Even in seemingly “normal” brain regions, neurons showed subtle signs of mitochondrial stress.

3. A Surge in B Cells and T Cells
Beyond microglia, the researchers observed increased infiltration of lymphocytes, particularly CD79A+ B cells and CD3+ T cells, in normal-appearing white matter. This hints that rs10191329AA carriers’ immune systems stay in a heightened inflammatory state even outside obvious lesions.

he Molecular Connection: DYSF, ZNF638, and Mitochondria
DYSF — The Cellular “Repairman”
The DYSF gene encodes DYSFerlin, a protein crucial for repairing damaged cell membranes. In muscle, mutations cause muscular dystrophy, but in the brain, its role has been less clear.

In this study, DYSF expression was elevated in neurons of rs10191329AA carriers, suggesting that the brain might be trying — and struggling — to repair ongoing cellular damage.

ZNF638 — A Viral Silencer With a Neural Twist
ZNF638, on the other hand, is a transcription factor known for helping silence viral DNA within cells via the HUSH complex. This is intriguing because Epstein-Barr virus (EBV) infection has long been implicated as a key environmental trigger for MS.

The researchers found more ZNF638-positive oligodendrocytes — the cells that make myelin — in the white matter of rs10191329AA donors. This might reflect an immune response attempting to suppress viral reactivation in MS-affected brains.

Mitochondrial Stress — The Energy Crisis Within
When the team sequenced nuclear RNA from neurons and oligodendrocytes, they discovered something unexpected: a global upregulation of mitochondrial genes in rs10191329AA carriers.

This pattern mirrors that seen in Leber’s Hereditary Optic Neuropathy (LHON) — a mitochondrial disease leading to optic nerve degeneration. It suggests that energy metabolism breakdown might underlie the accelerated neuronal loss seen in severe MS.

What It All Means: Linking Genes to Disease Progression
Altogether, these findings paint a picture of a brain under siege — where a genetic predisposition (rs10191329AA) amplifies inflammation, mitochondrial stress, and neuronal vulnerability.

The variant doesn’t just influence the immune response — it appears to also weaken neurons’ and oligodendrocytes’ ability to cope with metabolic and oxidative stress. This dual effect could explain why rs10191329AA carriers experience faster neurodegeneration even when inflammation is controlled.

Why This Matters for MS Treatment
Current MS therapies largely focus on modulating the immune system, which can reduce relapses but often fails to halt long-term disability.

By revealing how a specific genetic variant ties together inflammation, neurodegeneration, and mitochondrial DYSFunction, this study opens up new therapeutic targets — such as:

Boosting mitochondrial resilience in neurons and oligodendrocytes

Regulating DYSFerlin-mediated membrane repair mechanisms

Modulating ZNF638 or antiviral responses to prevent excessive cellular stress

As senior author Dr. Joost Smolders puts it, understanding variants like rs10191329 “helps connect the dots between genetics and the cellular pathology driving progressive MS.”

The Bigger Picture
Not all MS progression is written in the genome — but genetic variants like rs10191329AA help illuminate why some patients’ disease course is so relentless.

By combining genetics, neuropathology, and molecular profiling, Engelenburg et al. show that MS progression isn’t merely about immune attack — it’s also about how well the brain’s own cells withstand damage and repair themselves.

In other words: the future of MS therapy may lie as much in protecting neurons as in calming the immune system.

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:
Engelenburg, H. J., van den Bosch, A. M., Chen, J. A., Hsiao, C. C., Melief, M. J., Harroud, A., ... & Smolders, J. (2025). Multiple sclerosis severity variant in DYSF-ZNF638 locus associates with neuronal loss and inflammation. iScience, 28(5).