Nager syndrome (NS) is a very rare genetic condition that leads to developmental challenges and unusual structures in facial bones and limbs. While the gene responsible for the disorder is identified, the specific mechanisms remain poorly understood. Researchers from Japan utilized genetically modified zebrafish to reveal that the mutation involved in NS reduces the levels of Fgf8. This reduction subsequently alters the expression of an important group of cells known as neural crest cells, which play a critical role in facial development.
Nager syndrome, abbreviated as NS, is an uncommon hereditary disorder impacting the formation of the face and limbs, typically resulting in irregularities in the jaw, cheek, and hand bones. With fewer than 100 documented instances, our understanding of this condition is limited, largely focusing on mutations in the SF3B4 gene as the primary factor. Recently, a study published online on September 15, 2024, and featured in the November issue of the International Journal of Biological Macromolecules, from Kyushu University has created a promising method to investigate the fundamental mechanisms of this extraordinarily rare condition.
Using animal models is often the most effective strategy for researching diseases and their corresponding genes. Zebrafish serve as a common model organism due to the similarities in genetic disorders that impact mammals and zebrafish, providing valuable insights into complex diseases.
The researchers in this investigation observed that zebrafish display genetic and embryonic characteristics akin to mammalian facial and skull development. This similarity suggested that zebrafish could serve as an appropriate model for NS.
Consequently, an international team led by Associate Professor William Ka Fai Tse from Kyushu University’s Faculty of Agriculture genetically modified zebrafish to contain a mutated sf3b4 gene, resulting in an expression closely resembling human NS. “Our group utilized a zebrafish model to uncover the origins of this uncommon craniofacial condition. We sought to identify crucial molecules involved in the disease’s emergence and progression, as well as potential treatments to alleviate its severity,” says Dr. Zulvikar Syambani Ulhaq, a JSPS Invitational Research Fellow at Kyushu University and the principal author of the study.
After developing the animal model, the team carried out a comprehensive series of experiments to compare biospecimens with and without the mutation.
Through detailed analysis of cellular stress, skeletal structure, and cell death, the researchers found that zebrafish lacking sf3b4 had lowered levels of the gene fgf8. This reduction impacted the expression of neural crest cells (NCCs), which are vital for early facial structure development. Their misregulation could be significantly associated with NS features.
Additionally, the team discovered that excessive oxidative stress led to increased cell death in sf3b4-deficient zebrafish, possibly exacerbating the pathology of NS. Importantly, administering human-derived FGF8 to the mutant zebrafish considerably lessened NS features, suggesting a promising therapeutic approach for the condition.
Tse emphasizes the necessity of basic research in lesser-known diseases, noting that even small insights can significantly impact the lives of affected individuals. He adds, “Unlike more common conditions like cancer or diabetes, rare diseases such as NS are not prioritized by pharmaceutical companies, which often leads to the neglect of the few patients who suffer from them. Our research aims to illuminate this disease and instill hope in patients.”
Tse’s team is eager to forge partnerships and welcome contributions from various stakeholders, including clinical practitioners, patients, families, and basic researchers. “If you resonate with our mission and wish to aid research in rare diseases, we encourage you to reach out to us,” he states.
