In the quiet corridors of laboratories at the University of Barcelona, researchers have just solved a decade-long puzzle: what the HERC2 gene actually does inside our cells, and why mutations in it cause a constellation of devastating neurodevelopmental problems.
For years, doctors and scientists knew that genetic mutations in both copies of HERC2 triggered a rare syndrome marked by global developmental delay, intellectual disability, autism spectrum traits, and movement disorders—a condition strikingly similar to the better-known Angelman syndrome. Yet without understanding the gene's underlying biology, therapeutic strategies remained out of reach, locked behind a wall of cellular mystery. Now, a team led by José Luis Rosa, a professor at UB's Faculty of Medicine and Health Sciences and principal investigator of the Cell Signaling and Bone Biology Group at IDIBELL (the Bellvitge Biomedical Research Institute), has deciphered that mechanism, opening a potential pathway toward treatment.
The breakthrough centers on a crucial cellular housekeeping task: protein quality control. Using advanced quantitative proteomics techniques, Rosa's team—including lead researchers Joan Sala-Gaston and Laura Costa-Sastre—identified which proteins the HERC2 gene regulates. The findings, published in Cell Death Discovery, reveal that HERC2 acts as a cellular inspector, recognizing protein subunits that have not yet been properly assembled and marking them for elimination through the proteasome system, which serves as the cell's recycling center.
The mechanism is elegant and vital. "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," Dr. Rosa explains. When HERC2 functions normally, it ensures that malformed proteins don't accumulate and gum up cellular machinery. When mutations disable this gene, the system falters. Proteins that should be degraded linger in the cell, throwing off the delicate internal balance and crippling proteasome activity itself—creating a cascade of dysfunction that manifests as developmental delay, intellectual disability, and neurological symptoms in affected children.
The researchers reinforced this conclusion by testing cells derived from patients carrying a common HERC2 pathogenic variant. "The patient samples showed exactly the same problems in the protein degradation system, and abnormal proteasome activity," Sala-Gaston reports. This direct link between HERC2 mutations and broken protein degradation provides the missing piece of the puzzle that clinicians and researchers have been seeking.
HERC2 is part of a larger family of genes—including HERC1—that encode ubiquitin E3 ligase-like enzymes linked to various neurodevelopmental disorders. Understanding HERC2's role illuminates not just one rare syndrome but a wider category of genetic diseases rooted in faulty protein quality control. The study also identified the many protein complexes HERC2 regulates, spanning machinery for translation, vesicular transport, centrosome formation, and cytoskeleton structure—suggesting the gene's influence extends far beyond what was previously imagined.
For families raising children with HERC2-related neurodevelopmental disorder, this research marks the first real window into what's happening at the molecular level. That understanding is the essential foundation for developing targeted therapies. The answers are no longer hidden.