Four decades after a rare neurological disorder first surfaced, an Oklahoma Medical Research Foundation scientist has determined its cause thanks to tiny flies.
Scientist Wan Hee Yoon, Ph.D., used Drosophila, the common fruit fly, to pinpoint a genetic mutation that more recently caused severe developmental and metabolic issues in four children of Middle Eastern descent.
“This discovery was made possible by the Human Genome Project, which gives us the computational ability to unravel genetic mutations,” Yoon said. “Previously, it would have been impossible to identify this mutation as the cause with any certainty.”
Scientists first reported on the disorder in 1982 after studying the symptoms of siblings born to a Tunisian couple. Researchers said the children initially showed normal gait and speech development, but by age 5, a progressive neurological disorder had stolen their language and motor skills.
Scientists ultimately associated their symptoms – and those of children in a few subsequent studies – with a deficiency of an enzyme produced by the gene OGDH.
The most recent study involved four unrelated children. Severe abnormalities first appeared during infancy for all four, ranging from an abnormally small brain to decreased muscle tone to acid buildup caused by kidney failure. One child died before their first birthday.
Using cutting-edge genetic sequencing technology, Yoon and his colleagues determined that each patient had recessive mutations in the OGDH gene, which strongly suggested the disease’s cause. Fruit flies helped him prove it.
About 75% of the fruit fly’s genes mirror those in humans. Yoon removed the flies’ counterpart gene to the relevant human gene and introduced the mutations found in the human patients. Doing so left the fruit flies with symptoms similar to the human patients.
Yoon previously used fruit flies to discover genetic mutations as the cause of two rare diseases that bear his name: Harel-Yoon syndrome and Yoon-Bellen syndrome.
“Dr. Yoon is an extremely bright researcher, and his discovery was a collaborative effort between scientists, physicians and patient families, all of whom share a goal of advancing our understanding of disease,” said OMRF scientist Benjamin Miller, Ph.D., who leads OMRF’s Aging and Metabolism Research Program. “This was the first step toward hopefully modulating the genetic pathway and perhaps someday preventing this disorder.”
The findings were published in the journal Genetics in Medicine. Two former OMRF scientists, Madison Chilian and Helga Progri, played key roles in the research.
The research was supported by National Institutes of Health grants 5R01 NS121298-02 and 5 P20 GM103636-09, with additional funding from the Presbyterian Health Foundation and the Oklahoma Center for Adult Stem Cell Research, a program of the Oklahoma Tobacco Settlement Endowment Trust.
