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Nager syndrome, or NS, is a rare genetic disease that affects the development of the face and limbs, usually causing anomalies in the bone structures of the jaws, cheeks, and hands. With a prevalence of less than 100 cases ever reported, not much is known about the disease except the fact that mutations in the SF3B4 gene are its primary cause. Now, in a recent study made available online on September 15, 2024 and upcoming in the November issue of International Journal of Biological Macromolecules, researchers from Kyushu University have developed a convenient approach to explore the underlying mechanisms of this extremely rare disease.
When studying diseases or genes related to diseases, using animal models is often the best approach. The zebrafish is one such commonly used animal model. This is because many genetic disorders that affect mammals affect zebrafish in virtually the same way, allowing scientists to shed light into the nitty gritty of complex diseases.
In the present study, the researchers noted that the genetic and embryonic features of how the face and skull develop in zebrafish are similar to those in mammals. This, in turn, suggested that zebrafish could be used to model NS.
Accordingly, an international research team led by Associate Professor William Ka Fai Tse from Kyushu University’s Faculty of Agriculture, genetically engineered zebrafish to carry a mutated sf3b4 gene, resulting in a condition closely mirroring human NS. “Our group employed a zebrafish model to unfold the pathogenesis of this rare craniofacial disease. We aimed to identify molecules that play critical roles in the disease’s development and progression, along with potential therapies to reduce its severity,” explains Dr. Zulvikar Syambani Ulhaq, a JSPS Invitational Research Fellow at Kyushu University and the first author of the study.
Once the animal model was established, the team conducted an extensive series of experiments to compare mutated and non-mutated specimens.
After careful analyses of cellular stress, bone structure, and apoptosis, the researchers determined that sf3b4-deficient zebrafish have suppressed levels of the gene fgf8. This in turn affects the expression pattern of a type of cells called neural crest cells (NCCs). NCCs play an essential role during the early development of the facial structure, and their dysregulation could be strongly linked to the features of NS.
Moreover, the team found that apoptosis triggered by excessive oxidative stress was more prominently detected in sf3b4-deficient zebrafish, possibly contributing to the pathogenesis of NS. More importantly, injecting mutant zebrafish with human-derived FGF8 significantly reduced NS features, hinting at a potential therapeutic strategy for the disease.
Tse highlights the importance of conducting basic research in less explored diseases, since the little insights that we gather can make all the difference in the lives of those affected. He further explains, “Unlike cancer or diabetes, rare diseases like NS are not priority research objectives among pharmaceutical companies, and the small groups of patients suffering from them are always overlooked. Our work sheds important light on this disease and can bring hope to those patients.”
Tse’s group welcomes collaborations and donations from various parties, from clinical doctors, patients, families to basic researchers. “If you agree with our concept and would like to contribute to the basic research in rare diseases, we encourage you to contact us,” he says.