Publication Date

8-6-2021

Journal

Science

DOI

10.1126/science.aba4991

PMID

34353949

PMCID

PMC9714245

PubMedCentral® Posted Date

12-1-2022

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Acetylgalactosamine, Animals, Biopterins, Diet, Disease Models, Animal, Female, Hepatocytes, Humans, Liver, Male, Mice, Mice, Knockout, Nucleic Acid Conformation, Phenylalanine, Phenylalanine Hydroxylase, Phenylketonurias, Protein Binding, RNA, Long Noncoding

Abstract

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. We demonstrated that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine, musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell (hiPSC)-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive phenylalanine in Pair−/− and PahR408W/R408W mice and improved the phenylalanine tolerance of these mice.

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