HMN 2026: What is the HERC2 gene’s key role in rare neurodevelopmental syndrome

For years, it has been known that mutations in both copies of the HERC2 gene are associated with a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, features of the autism spectrum and movement disorders—characteristics very similar to those of Angelman syndrome, a better-known but equally rare condition. However, the exact function of the affected gene (HERC2) and the molecules with which it interacts remained unclear. Without understanding the biology underlying the syndrome, it was difficult to comprehend how it works and to devise therapeutic strategies to treat it.

Researchers from the University of Barcelona and the Bellvitge Biomedical Research Institute (IDIBELL) at the Bellvitge Campus have now studied the role of the HERC2 gene in neurodevelopmental disorders of this type, identifying its key role in the selective degradation of proteins—the “quality control” of proteins within the cell—which is carried out via the proteasome system.

The study, published in the journal Cell Death Discovery, was led by José Luis Rosa, a professor at the UB’s Faculty of Medicine and Health Sciences and principal investigator of the Cell Signaling and Bone Biology Group at IDIBELL. The research, with Joan Sala-Gaston and Laura Costa-Sastre as lead authors, marks the first steps toward unraveling the biology of disorders caused by this gene.

A family of genes linked to various neurodevelopmental disorders

Pathogenic variants in the HERC1 and HERC2 genes, which encode ubiquitin E3 ligase-like enzymes, have been associated with different neurodevelopmental diseases. In the case of HERC1, genetic alterations in both copies of the gene cause a rare syndrome characterized by macrocephaly, dysmorphic facial features and psychomotor retardation.

In the case of HERC2, variants in both copies of the gene that reduce its function are associated with a neurodevelopmental disorder with features similar to Angelman syndrome, including global developmental delay, intellectual disability, autism spectrum traits and movement disturbances. Despite this relationship with various pathologies, however, until now little was known about which proteins HERC2 regulates and, therefore, how these alterations contribute to the disease.

To address this question, the researchers used advanced quantitative proteomics techniques to identify ubiquitin-tagged proteins—a signal that in many cases directs proteins toward degradation. Through this approach, they identified numerous proteins in HERC2-regulated protein complexes important for cell functioning, such as the proteasome and the machinery for tRNA synthesis, initiation of translation, vesicular transport, and formation of centrosomes and the cytoskeleton, among others.

Error identified: Protein quality control fails

Among all these systems, the correct functioning of the proteasome stands out as the main functional target of HERC2. The results show that the HERC2 protein recognizes protein subunits that have not yet been properly assembled and marks them for elimination, a process that depends on interaction with chaperone-like proteins.

“Basically, the function of HERC2 is to detect defective proteins and mark them with a tag (ubiquitin) that indicates that they are not well assembled and, therefore, have to be degraded,” explains Dr. Rosa. This mechanism is essential to ensure proper assembly of the proteasome and, above all, to maintain protein balance within the cell. “Therefore, when HERC2 does not work properly, this balance is altered, proteins that should be degraded accumulate, and the activity of the proteasome is affected,” he adds.

These conclusions have been reinforced by experiments conducted on cells derived from patients carrying a common pathogenic variant of the HERC2 gene. “The patient samples showed exactly the same problems in the protein degradation system, and abnormal proteasome activity,” says Sala-Gaston, a postdoctoral researcher and first author of the study.

Overall, the study establishes a direct link between alterations in the HERC2 gene and the functioning of the protein degradation system, providing new insights into the molecular mechanisms that can cause the neurodevelopmental disorders seen in patients. In this sense, the work is part of IDIBELL’s commitment to strengthening research into rare pathologies through the REMMA Bellvitge program (Transversal Research Program in Adult Rare Diseases).

Although there is still a long way to go, “understanding the biological basis of this rare syndrome is the necessary step to be able to design, in the future, therapeutic strategies capable of restoring protein balance and improving the lives of patients,” concludes Costa-Sastre, a predoctoral researcher and first author of the study.

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