Researchers discover new factor in preventing phenylketonuria, offering
new treatment strategy
Study first to discover long noncoding RNA regulates phenylalanine metabolizing enzyme

Date:
August 5, 2021
Source:
University of Texas M. D. Anderson Cancer Center
Summary:
Researchers have discovered a critical new factor in regulating
metabolism of the amino acid phenylalanine and, therefore, in
preventing the inherited metabolic disorder phenylketonuria. The
research suggests a possible avenue for new treatments.



FULL STORY ========================================================================== Researchers at The University of Texas MD Anderson Cancer Center
have discovered a critical new factor in regulating phenylalanine
metabolism and, therefore, in preventing the inherited metabolic disorder phenylketonuria (PKU). The research also suggests a possible avenue for
new treatments that may be effective for certain patients with PKU.


==========================================================================
The study, published today in Science, demonstrates that the long
noncoding RNA (lncRNA) HULC directly regulates the metabolic enzyme phenylalanine hydroxylase (PAH). Loss of the lncRNA resulted in excess phenylalanine and symptoms consist with PKU in model systems, whereas
applying synthetic mimics of HULC restored PAH activity and lowered phenylalanine levels.

"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, Ph.D., 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." Long noncoding RNAs
are a form of RNA that do not encode a protein, but instead perform a
variety of regulatory roles within the cell. Interested in identifying
lncRNA with important biological functions, the researchers began this
study by profiling lncRNAs expressed in various organs, both in early
life and adulthood.

They discovered HULC,and its murine equivalent Pair, were highly
expressed in the adult liver. Hypothesizing this lncRNA may act as
a tumor suppressor, the researchers genetically deleted Pairin mouse
models. However, rather than developing liver cancer, the Pairknockouts
instead developed metabolic symptoms consistent with PKU.

Phenylketonuria and its milder variant hyperphenylalaninemia (HPA)
are inherited metabolic disorders marked by an inability to convert
the amino acid phenylalanine into tyrosine. These conditions affect
roughly 1 in every 10,000 infants, most of whom have mutations in the PAH
gene. Untreated PKU can lead to brain damage, intellectual disabilities, seizures and behavioral or psychiatric disorders. However, the only
treatments available are a protein-restricted diet and/or supplementation
with BH4 -- a PAH cofactor.



==========================================================================
Upon further examination, the researchers confirmed that Pair knockouts
had excessive levels of phenylalanine. Biochemical studies demonstrated
that both Pairand HULCbind directly to the PAH enzyme, enhancing its
ability to convert phenylalanine into tyrosine.

"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, M.D., Ph.D., 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." The lncRNA mimics used in the study are synthetic nucleotides designed to be more stable and home to the liver for targeting PAH. To
further investigate this approach as a possible treatment strategy,
the researchers created a mouse model of PKU, carrying the most commonly
found mutation in PAH. The HULCmimic improved phenylalanine metabolism
as evidenced by a sustained reduction in phenylalanine levels.

Based on these results, the researchers anticipate that HULCmimics may be
a useful strategy in treating patients with mutations in both the lncRNA
as well as the PAH enzyme. In collaboration with experts at the University Hospital of Nancy Reference Center for Inborn Errors of Metabolism (Nancy, France), the team is working to determine the prevalence of HULCmutations
in patients with PKU as a possible alternate cause of the disease.

The team also is pursuing additional laboratory studies to advance
HULCmimics toward future clinical studies to evaluate safety and efficacy.

The study was led by Yajuan Li, Ph.D., and Yaohua Zhang, Ph.D., both postdoctoral fellows in Molecular & Cellular Oncology, and Zhi Tan,
M.D., Ph.D., now at the Baylor College of Medicine. A complete list of collaborating authors and their disclosures can be found with the full
study here.

This research was supported by the National Institutes of Health (NIH) (1S10OD012304-01, P30CA125123, R01CA225955), the Cancer Prevention &
Research Institute of Texas (CPRIT) (RP170005, RP150085, RP190570,
RP170333), the National Science Foundation (CHE-1411859), the Andrew
Sabin Family Fellowship, and institutional support from MD Anderson,
the University of Houston and the Baylor College of Medicine.

========================================================================== Story Source: Materials provided by University_of_Texas_M._D._Anderson_Cancer_Center. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Yajuan Li et al. A noncoding RNA modulator potentiates phenylalanine
metabolism in mice. Science, 2021 DOI: 10.1126/science.aba4991 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210805141205.htm

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