#USA #New York #NYU Langone Health #genetic mutations #Hirschsprung disease

New Modeling Approach Reveals Insights into Hirschsprung Disease Mechanisms

A significant advancement in understanding Hirschsprung disease (HSCR) comes from a team at NYU Langone Health. This rare condition arises from the improper development of the enteric nervous system (ENS) during digestive system formation. The ENS, often referred to as the “second brain,” is crucial for regulating gastrointestinal functions, and disruptions in its development can lead to severe intestinal blockages, especially in infants.

The traditional models used to study HSCR have primarily examined the role of individual genes in the disease's development. However, this new study—a collaboration led by Ryan Fine, PhD—proposes a more comprehensive strategy that focuses on the interactions among various genes. This innovative approach provides insights into how multiple genetic factors contribute to the onset and manifestation of HSCR, potentially paving the way for more effective treatments in the future.

The research unveils that specific genetic changes can affect the formation of nerves within the gut, with mutations in two key genes, RET and EDNRB, being central to the development of HSCR. Previously, studies conducted on animal models would deactivate either one of these genes entirely, but this only mirrored certain aspects of the human disease. Notably, these previous models did not capture the gender disparity observed in human cases—where the disease is reported to be four times more prevalent in males or the fact that it predominantly affects the lower regions of the colon.

The researchers decided to employ a more nuanced method by creating models with varied mutations in both RET and EDNRB. This approach led them to a model that more closely replicated the human condition, with a focus on partial functionality and different combinations of mutations rather than complete loss. Their findings were groundbreaking: they identified that in the most effective model, where one RET gene copy was inactivated while both EDNRB copies remained partially functional, the resulting mice displayed the expected symptoms of HSCR, such as lower intestinal blockage, with a notable inclination towards male prevalence—mirroring human disease patterns.

Interestingly, while the genetically modified mice did not achieve complete nerve cell maturation, they did possess an unexpected surplus of immature nerve cells in their intestines. This discrepancy prompted further investigation into the molecular pathways influenced by the mutations. Through meticulous gene analysis, elevated levels of SOX2OT—a gene linked to nerve cell maturation—emerged as a potential contributor to the observed phenotype. The dysfunctional RET and EDNRB genes were suspected to fail in regulating SOX2OT effectively, hence hampering the maturation process of progenitor cells into mature nerve cells necessary for a fully developed ENS.

Dr. Aravinda Chakravarti, a veteran in HSCR research, led this study and aims to broaden the applicability of this multi-mutation approach beyond Hirschsprung disease to other developmental disorders. He emphasizes the idea that many complex human disorders arise from the compounding effects of mutations across several genes rather than the singular loss of function in one gene. Chakravarti shares, “This model serves as a template for examining various complex human disorders. Understanding these diseases through the lens of multiple small mutations could lead us closer to actionable treatments and interventions.”

The research, published in the journal PNAS, not only redefines the approach towards studying HSCR but also holds promise for other developmental diseases, highlighting the necessity of a multifaceted perspective in genetic research.

Funding for this compelling study was facilitated by the National Institutes of Health grant HD028088, exemplifying the crucial role governmental support plays in the advancement of medical research. The insights from this research create new avenues for understanding and potentially treating Hirschsprung disease, taking us a step closer to developing viable interventions for affected infants.

In summary, the NYU Langone Health research team’s comprehensive modal shift in studying HSCR deepens our understanding of the complexities surrounding genetic conditions and enhances our strategy towards future medical solutions. This encouraging breakthrough is not just pivotal for Hirschsprung disease but for a wider range of genetic disorders as well.