Multiple sclerosis (MS) is a complex neuroimmune disease, and for years, researchers have hunted for the precise genetic factors that increase susceptibility. Genome-wide association studies (GWAS) have pointed to dozens of genomic “hotspots” where risk variants tend to cluster. But finding the exact functional variant—the one that actually changes biology—is far harder.

A study by Matesanz et al. (2015) took on this challenge at the SP140 gene, a locus repeatedly linked to MS, Crohn’s disease (CD), and chronic lymphocytic leukemia (CLL). Their analysis reveals a striking story:

A single nucleotide change alters how SP140 pre-mRNA is spliced,

which reduces full-length SP140 protein production,

and this functional change appears to increase MS risk.

Let’s unpack what that means—and why it matters.

SP140: An immune-system chromatin reader with an unclear job description
SP140 is part of a family of proteins that live in nuclear bodies, specialized hubs that regulate gene expression in immune cells. Structurally, SP140 carries:

A CARD/HSR domain (often involved in protein–protein interactions),

A SAND domain (common in DNA-binding proteins),

A PHD finger and bromodomain, modules known for reading histone marks.

SP140 is highly immune-specific and has similarities to AIRE, a critical transcriptional regulator of immune tolerance. While its full function is still being mapped, hints suggest roles in:

Antiviral immunity,

Immune tolerance,

Chromatin-based regulation of inflammatory pathways.

This makes SP140 a compelling candidate gene for autoimmune risk.

The Genetic Puzzle: Many variants in the region, but which one drives disease?
GWAS had flagged the SP140 locus for:

Multiple Sclerosis (MS)

Crohn’s Disease (CD)

Chronic Lymphocytic Leukemia (CLL)

However, these studies identified different variants—all clustered within SP140—and many were in strong linkage disequilibrium (LD). This means they travel together in populations, making it hard to isolate the true causal variant.

Matesanz et al. overcame this by integrating:

Ultra-dense MS association maps from the Immunochip project

RNA-Seq–based expression quantitative trait loci (eQTLs) from GEUVADIS

Functional splicing assays
Protein-expression analysis in patient immune cells

This multi-layer approach allowed them to move beyond correlation to mechanistic causation.

A breakthrough: Two SP140 isoforms behave differently depending on genotype
The team discovered that two major SP140 RNA isoforms show opposite expression patterns depending on genotype at the key variant:

A full-length SP140 transcript (with exon 7)

An alternative transcript missing exon 7

Individuals with the MS-associated allele show:

Less full-length transcript

More exon-7-skipped transcript

This immediately raised a red flag: something in this region is altering splicing, not just overall gene expression.

The Smoking Gun: Variant rs28445040 disrupts normal splicing
After carefully comparing all variants in the LD block, the authors pinpointed rs28445040—located inside exon 7, just 5 nucleotides from the acceptor splice site.

Their experiments were compelling:

Exon-level eQTL analysis

Exon 7 showed the strongest genotype-dependent expression change among all SP140 exons.

RT-PCR in LCLs and PBMCs

Individuals with the risk allele consistently produced more exon-skipped transcript.

Minigene splicing assay

By inserting exon 7 (with either allele) into a splicing reporter system, they observed:

T (risk) allele → ~60% exon skipping

C (non-risk) allele → < 10% exon skipping

This cleanly demonstrated that rs28445040 itself is functionally disruptive to splicing.

Does altered splicing affect SP140 protein levels? Yes.

Western blot analysis of PBMCs from MS patients and controls showed:

Individuals with the risk TT genotype had significantly reduced SP140 protein

Only the full-length SP140 protein was detectable

The exon-skipped isoform did not produce a detectable protein—perhaps due to instability or antibody epitope issues. Either way, the functional consequence is clear:

The rs28445040 risk allele leads to reduced SP140 protein in immune cells.

But does this variant actually associate with MS? A 7,500-person study says yes.

To validate its clinical relevance, the authors performed a large Spanish cohort case-control study (4384 MS cases; 3197 controls). They compared:

The known GWAS variant rs10201872

The functional splicing variant rs28445040

Results:
Both showed similarly strong MS associations Both are in very high LD (r²=0.93) in Europeans Even sophisticated regression couldn’t statistically separate them—consistent with rs28445040 being the true driver.

Why would reduced SP140 contribute to MS?
The paper offers two major hypotheses—both plausible and not mutually exclusive:

Impaired immune tolerance (AIRE-like role)

Given SP140’s similarity to AIRE, decreased SP140 may compromise central or peripheral tolerance mechanisms, increasing susceptibility to autoimmunity.

Reduced antiviral response

SP140 has been linked to antiviral pathways, including interactions with HIV-1 Vif.

If SP140 participates in innate defense against viruses such as EBV—a suspected MS trigger—reduced levels could influence disease risk.

This fits broader evidence that:

EBV infection is nearly ubiquitous in MS patients

Endogenous retrovirus activation may interact with EBV in MS pathogenesis

Many MS-risk genes are interferon-responsive

Why this study matters
This work is exemplary for several reasons:

It identifies a true causal variant, not just an associated marker

A rare achievement in post-GWAS functional genomics.

It links genotype → splicing → transcript isoform → protein expression → disease risk

A complete mechanistic chain.

It suggests shared biological pathways between MS, CD, and CLL

Highlighting common immunogenetic roots across autoimmune and lymphoproliferative diseases.

It provides a framework for studying many other GWAS loci

Especially those involving alternative splicing—an underappreciated driver of disease risk.

Conclusion
Matesanz et al. uncover a precise mechanistic explanation for how a single nucleotide change—rs28445040—disrupts SP140 splicing, reduces protein production, and contributes to MS susceptibility. This study is a powerful reminder that:

Not all variants inside GWAS peaks are equal

Splicing variants are often the hidden drivers of immune-related disease

Integrative genomics + functional assays can turn association signals into actionable biology

As we continue to refine our understanding of MS genetics, SP140 stands out as a compelling node linking immune regulation, antiviral defense, and autoimmunity.

Disclaimer: This blog post is based on the information provided in the cited scientific article. It aims to provide an accessible summary of the research findings and should not be considered as definitive medical advice. For any health concerns, please consult with a qualified healthcare professional.

Reference:
Matesanz, F., Potenciano, V., Fedetz, M., Ramos-Mozo, P., Abad-Grau, M. D. M., Karaky, M., ... & Alcina, A. (2015). A functional variant that affects exon-skipping and protein expression of SP140 as genetic mechanism predisposing to multiple sclerosis. Human molecular genetics, 24(19), 5619-5627.