In this issue: Discover how tiny zebrafish are having a large impact on SDS research and treatment development!
Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you!
Understanding Shwachman-Diamond Syndrome Through Zebrafish Research
Shwachman-Diamond syndrome (SDS) is usually caused by mutations in the SBDS gene, but some patients have mutations in another gene called DNAJC21. Because SDS is so rare, and mutations in DNAJC21 are even more rare, researchers often use animals, known as model organisms, like fish, mice, fruit flies, or other animals to study it. Using model organisms to study SDS and other rare diseases helps scientists better understand the disease and develop potential treatments. This is why SDS Alliance, in collaboration with the Jackson Laboratory, is committed to generating a mouse model with mutations in the SBDS gene that scientists can use to understand SDS and ask important questions that will advance treatment development for SDS.
In the SDS & Science Snapshot this week, we are highlighting a new study published by scientists at the CHEO Research Institute (Ottowa, Canada) and colleagues which used zebrafish, a different model organism than mice, to investigate the impact of germline mutations in DNAJC21 on the development of SDS-related symptoms and identify potential treatment opportunities.
Why Zebrafish Are Important for SDS Research
Zebrafish are tiny fish that are often used in research because they share many genetic similarities with humans. Their fast growth and transparent embryos make them ideal for studying how genes work, particularly in conditions which affect the blood and bone marrow (like SDS). The use of zebrafish as a model organism for SDS and SDS-associated conditions is not new – zebrafish have been used as a model organism for SDS in previous research studies as well (here is a link to one example).
In this study, scientists used zebrafish to model SDS caused by mutations in the DNAJC21 gene. By creating zebrafish with similar mutations, researchers can observe the effects of these mutations in a living organism, which provides valuable insights into how the disease affects humans. For more information about the importance of zebrafish and other model organisms in research, you can watch the video below.
Key Findings and Potential New Treatment Opportunities
The researchers found that zebrafish with mutations in the dnajc21 gene (the zebrafish equivalent of DNAJC21) showed symptoms similar to those seen in SDS patients. These fish had lower numbers of certain types of blood cells, grew more slowly, and had other health problems. This shows that the dnajc21 gene in zebrafish is important for normal blood cell production and overall growth, just like the DNAJC21 gene in humans.
One of the exciting findings from this study is that the researchers identified a new role for the zebrafish dnajc21 gene in controlling the production of nucleotides, which are the building blocks of DNA and RNA. When nucleotide levels were low (as a result of mutations in the dnajc21 zebrafish gene), the zebrafish developed problems with blood cell production. However, when the researchers gave the fish extra nucleotides, their blood cell counts improved. This suggests that treatments aimed at increasing nucleotide levels might help manage SDS symptoms in humans.
The Role of p53 and its Impact on SDS
The study also explored the role of another gene shared between zebrafish and humans, TP53, which is known to be involved in cancer and cell death. When the researchers introduced a somatic tp53 mutation into the dnajc21-mutant zebrafish, they observed some improvement in blood cell counts. However, this also led to other problems, like the development of myelodysplastic syndrome (MDS), a condition where blood cells don’t mature properly and can lead to leukemia. This finding highlights the complex relationship between different genes in SDS and how they can influence the disease’s progression. For more information, you can review this previous SDS & Science Snapshot which discusses another study investigating the role of acquired (or somatic) TP53 mutations in individuals with SDS.
What This Research Means for SDS Patients and Families
Although this research is still in the early stages, it provides a valuable foundation for future research studies and potential new treatments development. Research using zebrafish and other model organisms help scientists understand SDS better and offers hope for new treatments. By uncovering how different genes contribute to SDS and SDS-associated conditions, researchers can develop more targeted therapies. For patients and families living with SDS, these findings are a step forward in finding ways to navigate life with SDS and improve treatments.
Ketharnathan S, Pokharel S, Prykhozhij SV, Cordeiro-Santanach A, Ban K, Dogan S, Hoang HD, Liebman MF, Leung E, Alain T, Alecu I, Bennett SAL, Čuperlović-Culf M, Dror Y, Berman JN. Loss of Dnajc21 leads to cytopenia and altered nucleotide metabolism in zebrafish. Leukemia. 2024 Aug 13. Epub ahead of print. PMID: 39138265.
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