As the COVID-19 pandemic wound down, an international partnership that included researchers at Vanderbilt University Medical Center set out to solve a medical mystery — the deaths of four children from a never-before-seen “error” of development.
The children were born in Turkey with a smaller-than-normal head size, cataracts, severe developmental delay, intellectual disability and epilepsy. Three children in one of two related families died in infancy.
A cousin who also had hearing loss, limited movement and severe loss of muscle tone, liver dysfunction, anemia and elevated lipid levels was hospitalized numerous times, received tube feeding and died before his 5th birthday.
Suspecting a genetic abnormality, the Turkish physicians, working with colleagues in Germany, collected and sequenced DNA samples from both families — and got a hit. Both sets of parents carried a variation in SEC24C, a gene involved in the recognition, packaging and transport of essential proteins during development and throughout life.
To prove the variation was the cause of this fatal, unnamed disease, the German researchers called in Ela Knapik, MD, professor of Medicine at VUMC, whose lab is internationally known for its expertise in modeling rare diseases in zebrafish.
Zebrafish embryos, which are transparent and develop rapidly outside of the mother fish, are an efficient model for studying genetic and environmental factors that influence early development.
Knapik’s colleagues, led by senior research scientist Dharmendra Choudhary, PhD, research assistant Cory Guthrie and graduate student Taylor Nagai, used CRISPR-Cas9, a genome-editing technique, to functionally inactivate the corresponding SEC24C gene in zebrafish embryos.
Adult zebrafish lacking the gene had smaller brains, cataracts and loss of mobility — characteristics that reflected the human condition.
With these findings, researchers led by Nina Bögershausen, MD, and Bernd Wollnick, MD, at the Institute of Human Genetics in Göttingen, Germany, along with colleagues in Canada, studied what happens in human cells when the transport protein expressed by SEC24C is lacking.
This spring in JCI Insight, a journal of the American Society for Clinical Investigation, the researchers reported that a deficiency of this protein disrupted the modification and trafficking of “cargo” proteins essential for normal development, and explained the abnormalities observed in the children of the Turkish families.
While there is no cure, the multidisciplinary, transcontinental research that enabled this discovery may lead to improved treatments, not only for rare diseases like this, but also for more common, complex conditions such as movement disorders or epilepsy, Knapik said.
The research was supported in part by the National Institutes of Health (grants R01MH113362 and R56AG068026).
