OHSU researchers link three rare neurological disorders, identify potential therapeutic venue

According to the National Institutes of Health, one in 10 Americans is impacted by one of more than 7,000 identified rare diseases. The majority of these diseases are genetic and do not have approved treatments.

Expression of the steatosis target genes of MLL4
Ube3a-tg livers show suppressed expression of the steatosis target genes of MLL4, while Ube3a+/- livers show the opposite.

A novel study, led by Jae W. Lee, Ph.D., a professor of pediatrics in the OHSU School of Medicine and OHSU Doernbecher Children’s Hospital, has identified a metabolic link between three rare neurological disorders: Kabuki Syndrome (caused by reduced levels of MLL4), Angelman Syndrome (caused by reduced levels of UBE3A) and Dup15q (caused by enhanced levels of UBE3A).

The study results, which have published online in the journal Hepatology, identify the first potential pathway for treatment of each condition.

Using a mouse model, Lee and colleagues from the Pape Family Pediatric Research Institute and Vollum Institute at OHSU, found that the enzyme UBE3A plays a significant role in breaking down MLL4, an epigenetic regulator responsible for aspects of obesity and fatty liver formation.

Based on this finding, the team also predicted that decreased levels of MLL4 likely contribute to the abnormal skeletal facial features apparent in both Kabuki Syndrome and Dup15q. Further, elevated levels of MLL4 are predicted to promote weight gain, as well as a number of neurological challenges including minimal speech and frequent smiling and laughter, in patients diagnosed with Angelman Syndrome.

While additional study is necessary, the identification of MLL4 as the likely link across all three conditions leads Lee to believe that the UBE3A-MLL4 regulatory axis may provide a unique therapeutic venue for treating various MLL4-directed pathogeneses, including obesity and hepatic steatosis.

Earlier this year, in a study published May 23, 2018, in Nature Communications, Lee’s team demonstrated that two neurons key to growth and metabolism — GHRH and AgRP — are developmentally interconnected

In addition to Lee, other OHSU researchers involved in the study include Janghyun Kim, Dae-Hwan Kim, Ph.D., Younjung Park, B.A., Yuna Lee, M.S., and Soo-Kyung Lee, Ph.D. Colleagues from the University of Pittsburgh, the Korea Institute of Science and Technology and Seoul National University also contributed to this work.

Tracy Brawley

This study was funded by grants from the National Institute of Neurological Disorders and Stroke (R01 NS054941) and the National Institute of Diabetes and Digestive Kidney Diseases (R01 DK064678, R01 DK103661), both components of the National Institutes of Health; and the Korea Health Technology R&D Project through the Korea Health Industry Development,  funded by the Ministry of Health & Welfare, Republic of Korea (HI17C0447).