Phenylketonuria (PKU) is a rare inherited disorder that causes an amino acid called phenylalanine to build up in the body. PKU is caused by a defect in the gene that helps create the enzyme needed to break down phenylalanine. Now, scientists at the University of Texas MD Anderson Cancer Center have discovered a new factor in regulating phenylalanine metabolism, which will guide researchers in preventing PKU.

Their findings are published in the journal Science in a paper titled, “A noncoding RNA modulator potentiates phenylalanine metabolism in mice.” The study was led by Yajuan Li, PhD, and Yaohua Zhang, PhD, both postdoctoral fellows in molecular & cellular oncology, and Zhi Tan, MD, PhD, now at the Baylor College of Medicine.

“The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including PKU, is unknown,” wrote the researchers. “Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH).”

“There is a growing appreciation for the role of long noncoding RNAs in a variety of human diseases, but this is the first discovery of any long noncoding RNA involved with PKU,” said co-senior author Liuqing Yang, PhD, associate professor of molecular & cellular oncology. “Our research not only shows that HULC plays a very important role in PKU, but that we may be able to apply this discovery toward developing new treatments for patients who desperately need them.”

The researchers discovered HULC, and its murine equivalent Pair, were highly expressed in the adult liver. Hypothesizing that this lncRNA may act as a tumor suppressor, they genetically deleted Pair in mouse models. The Pair knockouts developed metabolic symptoms consistent with PKU instead of liver cancer.

“Phenylalanine hydroxylase has long been known to be regulated by allosteric factors, but we didn’t know what those factors were until now. This represents the first identification of a non-substrate factor regulating PAH,” said co-senior author Chunru Lin, MD, PhD, associate professor of molecular & cellular oncology. “Synthetic mimics of HULC were able to partially restore enzymatic activity in 13 of 17 different PAH mutants in vitro, representing some of the most frequent mutations seen in PKU.”

In collaboration with researchers at the University Hospital of Nancy Reference Center for Inborn Errors of Metabolism (Nancy, France), the team is working to determine the prevalence of HULC mutations in patients with PKU as a possible alternate cause of the disease.

The researchers are looking to the future and hope to continue to pursue additional laboratory studies to advance HULC mimics toward future clinical studies to evaluate safety and efficacy. The research suggests a potential path for new treatments that may be effective for certain patients with PKU.