A noncoding RNA modulator potentiates phenylalanine metabolism in mice.
Yajuan LiZhi TanYaohua ZhangZhao ZhangQingsong HuKe LiangYao JunYouqiong YeYi-Chuan LiChunlai LiLan LiaoJianming XuZhen XingYinghong PanSujash S ChatterjeeTina K NguyenHeidi HsiaoSergey D EgranovNagireddy PutluriCristian CoarfaDavid H HawkePreethi H GunaratneKuang-Lei TsaiLeng HanMien-Chie HungGeorge A CalinFares NamourJean-Louis GuéantAnia Carolina MuntauNenad BlauVernon Reid SuttonManuel SchiffFrançois FeilletShuxing ZhangChunru LinLiuqing YangPublished in: Science (New York, N.Y.) (2021)
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.
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