A noncoding RNA modulator potentiates phenylalanine metabolism in mice

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine (Phe), 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-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 Phe in Pair(-/-) and Pah(R408W/R408W) mice and improved the Phe tolerance of these mice.

Automated summary

This study reveals the functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders such as phenylketonuria (PKU) by showing their association with the metabolic enzyme PAH. Depletion of specific lncRNAs led to PKU-like symptoms in mice and reduced enzymatic activities of PAH in human liver cells. Therapeutic strategies using designed lncRNA mimics showed promising results in alleviating excessive phenylalanine accumulation in PKU mice.