Lerner Research Institute News

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Advancing the Study of Rare Genetic Disorder Shwachman-Diamond Syndrome

Dr. Corey and team have successfully genetically engineered a model of zebrafish that mimics Shwachman-Diamond Syndrome pathologies observed in patients, which will help advance research into developing new therapies to treat the disease.


According to new findings published in JCI Insight, Departments of Cancer Biology and Pediatric Hematology & Oncology researchers have developed a novel preclinical model of Shwachman-Diamond syndrome (SDS), a rare inherited condition characterized by the inability to digest food properly, low white blood cell count and skeletal abnormalities. SDS is also a leukemia predisposition condition, increasing risk of developing myeloid neoplasia by a thousandfold.

While the genetic underpinnings of SDS are widely accepted, exactly how SDS-causing mutations contribute to disease pathology has remained poorly understood. This is in part because of the rare nature of the disease, its varied presentations (phenotypes) and a lack of preclinical models for study.

Here, the team—led by Seth Corey, MD, MPH, a practicing pediatric hematologist and researcher—present their zebrafish model of SDS, which helped to elucidate a new mechanistic link between disease genetics and pathology.

The need for a new model

Approximately 90 percent of SDS cases are caused by inherited mutations to both copies of the SBDS gene (termed biallelic mutations). Other genes associated with the disease include DNAJC21, EFL1 and SRP54, notably all of which are related to faulty protein synthesis.

To date, most groups that have attempted to engineer a model of SDS silenced SBDS expression. Unfortunately, however, they have found that complete SBDS genetic knockdown is lethal in preclinical models.

“Reliable preclinical models that closely mirror SDS development and progression seen in patients is critical for the advancement of research into this disease,” said Dr. Corey. “Currently, the only therapy option for patients with SDS is hematopoietic stem cell transplant, which still does not extend life expectancy beyond about 35 or 40 years. With a good preclinical model, we can better study the cellular pathways involved in SDS and identify targets for novel therapies.”

 Using gene editing technology to alter protein rather than gene expression

Here, Usua Oyarbide, PhD, a project scientist in the Corey lab and first author on the study, used CRISPR/Cas9 gene editing technology to successfully engineer an SDS model of zebrafish that copies the disease manifestations commonly observed in patients, including low white blood cell count, pancreatic atrophy (indicative of faulty digestion) and short stature.

Unlike some nonviable preclinical models of SDS where SBDS expression was knocked down completely, Drs. Corey’s and Oyarbide’s model did not prevent gene expression but instead prevented the expression of functional Sbds proteins (the proteins coded for the by the sbds gene).

The models survived through the equivalent of an early juvenile period in humans, much longer than any other model under development. As such, they identified a critical period (between 15 and 21 days post fertilization) where cell dysfunction and death related to Sbds protein loss presented in multiple tissues and resulted in premature mortality.

Further analysis revealed that this was due, at least in part, to increased expression of genes related to the Tp53 protein, which under normal conditions helps to regulate and control undesired cell growth and replication.

“Elevated levels of Tp53 suggests that in SDS, cells’ normally protective biological responses become too strong and result in widespread and uncontrolled cell death throughout many tissues in the body,” said Dr. Corey. “Future studies into how reducing Tp53 levels, or related downstream pathways, may prove valuable in the search for new therapeutic targets for treating SDS, underscoring the tremendous value of developing and validating reliable preclinical models.”

This study was supported in part by the National Institutes of Health, Department of Defense, Shwachman-Diamond Syndrome Foundation and the CURE Childhood Cancer Foundation.

Image: Zebrafish siblings at the same age showing mutants with (A) reduction in size, (B) pancreas atrophy with lower number of zymogen granules, and (C) reduction of the absorptive area in the digestive tract.

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