Scientists at Sanford Burnham Prebys Medical Discovery Institute have shown that cells from children with NGLY1 deficiency—a rare disorder first described in 2012—lack sufficient water channel proteins called aquaporins. The discovery was published in Cell Reports and may help explain the disorder’s wide-ranging symptoms—including the inability to produce tears, seizures and developmental delays—and opens new avenues to find therapies to treat the disorder.
“Our findings uncover a new and completely unexpected ‘job’ for NGLY1, which was originally thought to only cleave sugars from proteins,” says Hudson Freeze, Ph.D., director and professor of the Human Genetics Program at Sanford Burnham Prebys and senior author of the study. “This new information, which includes the molecular signals NGLY1 uses to drive aquaporin production, fundamentally shifts how we approach drug development. Most immediately, we can begin to screen for existing FDA-approved drugs that may increase aquaporin levels.”
The first patient with NGLY1 deficiency, then-four-year-old Bertrand Might, was diagnosed in 2012. The condition occurs when both copies of the NGLY1 gene contain mutations. As a result, children with NGLY1 deficiency produce little or no N-glycanase1—a protein that removes sugars from proteins during the cell’s regular recycling process. Today, approximately 60 people in the world have been identified with NGLY1 deficiency. There is no cure, and existing treatments only address a few of the disorder’s symptoms.
“This discovery is a giant leap forward in our understanding of NGLY1 deficiency and our ability to find a drug for the condition,” says Matt Might, Ph.D., Bertrand Might’s father and chief scientific officer of NGLY1.org, which funded the research. “In addition to exploring new treatment avenues, we can immediately start to test currently available drugs to see if they may help Bertrand and other children living with NGLY1 deficiency.”