Advances in research into Schaaf-Young syndrome, an ultra-rare disease that causes mental retardation and birth defects.

UB | Wednesday, May 22, 2024

A team from UB, IRSD and CIBERER confirms how mutations in the gene MAGEL2 —causes syndrome— They lead to the formation of truncated and nonfunctional proteins that accumulate in the cell nucleus and thus can aggravate the symptoms of those suffering from this pathology.

gene mutations MAGEL2which cause Schaaf-Yang syndrome (SYS) is an ultra-rare disorder that affects neural and cognitive development.– generate non-functional truncated proteins that tend to accumulate in the cell nucleus. In addition, this progressive accumulation of abnormal proteins can cause toxic effects in patients suffering from this syndrome, who suffer from birth defects, mental retardation, changes in facial features, sleep apnea, and joint contractures.

These advances in SYS research are reflected in a study published in the journal. Journal of Medical Genetics. The study was led by a team from the Faculty of Biology and the Institute of Biomedicine of the University of Barcelona (IBUB), the Sant Joan de Déu Research Institute (IRSJD) and the Network Biomedical Research Center for Rare Diseases (CIBERER). ). It should be remembered that this team also authored the publication of the first clinical guideline on Schaaf-Young syndrome (Journal of Medical Genetics2022), aimed at healthcare workers and families of children suffering from this pathology.

A better understanding of the function, genetic variants, and impact of nuclear retention of MAGEL2 protein will open new opportunities for the development of patient-specific gene therapies. to prevent altered protein synthesis and eliminate SYS, a disease that still has no cure.

Genetic mutations that cause shortening of proteins

General MAGEL2 It is located on chromosome 15, is expressed in the nervous system and produces the MAGEL2 protein, which is involved in the retrograde transport and recycling of proteins in the cytoplasm of neuronal cells. To date, more than eighty mutations of this gene have been registered in the scientific literature. MAGEL2some of which are repeated among patients. It is estimated that there are currently about 250 people diagnosed with Schaaf-Young syndrome worldwide.

New work done on human cells in vitro, confirms that almost all truncated proteins associated with Schaaf-Young syndrome lose part of their molecular structure due to genetic mutations. “MAGEL2 proteins Functional proteins have a complete molecular structure that allows them to interact with other proteins and perform their normal biological functions. They are usually found in certain places in the cytoplasm of the cell. mainly in subcellular compartments associated with the transport and processing of proteins,” details Suzanne Balcells, a professor in the Department of Genetics, Microbiology and Statistics at UB and co-ordinator of the work. “On the other hand,” he continues, “truncated proteins are shorter versions of the MAGEL2 protein because they have been affected by genetic mutations. Therefore, the truncated proteins are missing certain regions required to function properly in the cell.

Due to genetic mutations, truncated proteins lose key structural domains, such as the MAGE homology domain, which is critical for interactions with other proteins. ““The absence of this domain may prevent these interactions required for proper function of MAGEL2, such as its role in retrograde transport and protein recycling.” explains Roser Urreizti.

When toxic proteins accumulate in the cell nucleus

The truncated proteins tend to accumulate in the nucleus of the cell, and this can further worsen symptoms in people with Schaaf-Young disease. As Monica Centeno details: “It is likely that in a real cellular context, a portion of the synthesized truncated proteins can also be found in certain locations in the cytoplasm, such as endosomes. Now, since their structure has changed, they may not be able to perform their normal functions properly.“

The severity of clinical manifestations in patients with Schaaf-Young syndrome may be associated with the accumulation of altered proteins in the cell nucleus. “That is, all indications are that mutations that cause more severe symptoms also cause the truncated MAGEL2 protein accumulates more in the nucleus. This may be explained by the higher accumulation of truncated proteins in the nucleus. “This can interfere with important nuclear processes and have a greater impact on how the cell functions under normal conditions.”“says Raquel Rabionet.

In search of a cure for Schaaf-Young syndrome

Cellular mechanisms that control protein degradation, such as the ubiquitin-proteasome system,may help reduce the negative effects of truncated proteins and help mitigate the progression of pathology.. However, if the rate of protein production exceeds the cell’s capacity for degradation, aberrant proteins may escape degradation and continue to cause toxic effects. As Aina Prat explains, “In this sense, we confirmed that normal and truncated MAGEL2 proteins have very similar half-lives. Therefore, truncated MAGEL2 would be stable in the cell, where it could have toxic effects.”

“If we knew how truncated MAGEL2 proteins alter cellular function, strategies could be developed to promote the degradation of these toxic proteins, restore cellular function, or compensate for metabolic and signaling dysfunctions caused by their accumulation.”concludes the team, which will advance new research to contribute to the development of innovative treatments for people suffering from SYS.

Link to the product:

Centeno, Monica; Alcaide Consuegra, Estefania; Gibson, Sophie; Prat Planas, Aina; Gutierrez-Avila, Juan D.; Greenberg, Daniel; Urreizti, Roser; Rabionet, Raquel; Balcells, Suzanne. “Subcellular localization of truncated MAGEL2 proteins: insights into the molecular pathology of Schaaf-Young syndrome”». Journal of Medical Genetics, March 2024. DOI: 10.1136/jmg-2024-109898.