What if the key to treating a rare genetic condition lies not just in whether a protein is present—but in where it ends up inside the cell?
This is the case with the MAGEL2 protein, which plays a critical role in cell function and is missing or altered in two rare neurodevelopmental conditions: Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS). New research shows that in SYS, MAGEL2 protein doesn't just go missing—it goes to the wrong place. And that misdirection may make symptoms worse.
Why MAGEL2 Matters in PWS and SYS
MAGEL2 is one of the genes missing in individuals with Prader-Willi syndrome, meaning their cells can’t produce the MAGEL2 protein at all. In contrast, individuals with Schaaf-Yang syndrome do have the MAGEL2 gene—but it’s mutated. This results in the production of a truncated (partial) version of the protein.
That leads researchers to an important question: How does having a partial MAGEL2 protein affect cells differently than having none at all?
The Function of MAGEL2
One of MAGEL2’s major responsibilities is to help transport vesicles—tiny container-like structures within cells that carry hormones and neuropeptides. These molecules are critical for signaling between cells. Without MAGEL2, vesicle transport may be disrupted, leading to fewer signaling molecules and affecting how cells communicate.
Research suggests that in most SYS cases, the part of MAGEL2 responsible for vesicle transport is missing. This means that although SYS and PWS involve different underlying mechanisms, they may disrupt similar hormone and neuropeptide signaling pathways.
New Findings: MAGEL2 Builds Up in the Nucleus
In 2022, a Spanish research group showed that one MAGEL2 mutation (Gln638*) caused the protein to build up in the wrong part of the cell—the nucleus. Using fluorescent stains that color the nucleus, cytoplasm, and MAGEL2 protein differently, researchers could see that the mutant MAGEL2 was much more concentrated in the nucleus than the normal, full-length version.
More recently (2024), two studies expanded on these findings. The same Spanish group looked at five more MAGEL2 mutations and found that every one caused more MAGEL2 to accumulate in the nucleus. An Austrian team confirmed these findings using a different MAGEL2 mutation (Q666Pfs*47), again seeing “considerably higher nuclear accumulation.”
Why Does MAGEL2 Accumulate in the Nucleus?
Proteins often have built-in "address labels" that tell the cell where to send them. These include nuclear localization signals (NLS) and nuclear export signals (NES), which move proteins in and out of the nucleus. The typical MAGEL2 protein has both an NLS and an NES.
In most SYS mutations, the protein has the signal to enter the nucleus but not to leave—causing it to pile up there. Researchers suspect that this nuclear buildup, combined with reduced MAGEL2 activity in a different part of the cell (the cytoplasm), contributes to SYS symptoms.
In fact, studies have found that the more MAGEL2 builds up in the nucleus, the more severe the SYS symptoms may be—including the presence of contractures (arthrogryposis multiplex congenita) in the joints of people with SYS. These joint contractures are uncommon in individuals with PWS, where MAGEL2 is completely absent and therefore cannot accumulate in the nucleus.
What’s Next: Tracking and Targeting MAGEL2 Mislocalization
Now that we can visibly identify the differences between cells expressing truncated MAGEL2 and those with typical MAGEL2, we’ll be able to see when a treatment is able to correct where the MAGEL2 is located.
This summer, FPWR will launch our first project aiming to reduce or eliminate the truncated MAGEL2 protein from SYS cellular models. The GeneSYS project will screen antisense oligonucleotides (ASOs) to identify and evaluate possible treatment candidates. Promising candidates will then be advanced into animal models for preclinical testing to evaluate the benefits and risks of removing MAGEL2.
Concurrently, researchers are also exploring whether human MAGEL2 can function properly in rodent cells. If so, it may be possible to create a new, more accurate SYS model by replacing the rodent MAGEL2 gene with the human one—an important step toward treating the condition.
Looking Ahead
Research into MAGEL2 localization and function is helping scientists uncover the biological mechanisms behind Schaaf-Yang syndrome and providing new directions for therapy development. By understanding how MAGEL2 mutations alter protein behavior inside the cell, we’re taking meaningful steps toward targeted treatments—and ultimately, improved outcomes for individuals with SYS and their families.
