Gaucher subtypes driven by unique molecular signatures: Study
Finding could guide targeted approaches to treatment, researchers say
Written by |
The three main types of Gaucher disease differ not only in symptoms but also in the biological processes driving the disease at a molecular level, according to a study.
Type 1 Gaucher disease is associated with changes in immune regulation, tissue structure, and cellular stress responses, while types 2 and 3 show gene activity patterns linked to inflammation, brain development, and cell survival.
“The results might enhance our understanding of the molecular basis of [Gaucher disease] subtypes … and underscore the importance of personalized therapeutic approaches targeting specific disease mechanisms,” the researchers wrote.
The study, “Transcriptomic signatures in Gaucher disease subtypes: A systems biology perspective,” was published in Molecular Genetics and Metabolism Reports.
Gaucher disease is caused by mutations in the GBA1 gene, which provides the instructions for making the enzyme glucocerebrosidase (GCase). This enzyme is responsible for breaking down a fatty molecule called glucocerebroside (Gb1) into smaller components that cells can reuse. Without it, Gb1 and the related molecule lyso-Gb1 accumulate to toxic levels in tissues, causing a range of symptoms.
Types denote symptoms, severity
The three main types of Gaucher are classified based on the presence and severity of neurological symptoms. Type 1, the most common form, does not cause neurological symptoms, while type 2 and type 3 are more severe and involve the nervous system.
People with Gaucher exhibit many molecular-level changes compared with healthy individuals, but it remains unclear which biological pathways are specific to each subtype.
To gain more insight, a team of researchers in Iran examined gene expression — which genes are active and to what extent — in skin cells derived from patients with different Gaucher disease types. For comparison, they used publicly available gene expression datasets from healthy individuals.
The group identified many differentially expressed genes — those that were either more or less active in patients than in controls — that varied by disease type and age.
In cells from people with type 1 Gaucher disease, the researchers observed changes in genes involved in how cells process genetic information, maintain tissue structure, and respond to stress.
Genes involved in immune signaling, including pathways related to the production of signaling molecules and TGF-beta signaling, were less active, pointing to disrupted immune regulation.
These findings suggest that type 1 may be characterized by broad changes in cell organization, tissue structure, and immune balance.
A different pattern was observed for type 2 disease, the most severe form of Gaucher. Cells from these patients showed increased activity in genes linked to inflammation, immune activation, and tissue remodeling. These changes were consistent with widespread inflammatory damage and severe neuroinflammation, or inflammation affecting the brain.
In type 3 Gaucher disease, which has a less severe, slower progressing neurological course, gene expression patterns differed partly by age. In older patients, genes involved in the PI3K/AKT pathway, which regulates cell survival, metabolism, and growth, were more active. This suggests ongoing cellular adaptation to chronic stress.
In younger patients, changes were seen in genes related to nervous system development and myelination, the process that coats nerve fibers with a fatty sheath and supports signal transmission.
The study also identified so-called hub genes, genes that play central roles in coordinating multiple biological pathways. Several of these hub genes differed across disease types, suggesting they could serve as molecular markers or future therapeutic targets.
The findings suggest that Gaucher disease subtypes are driven by overlapping but distinct biological mechanisms, supporting the idea that treatments and monitoring strategies may need to be tailored more closely to disease type, the researchers said.
