A noncoding RNA modulator potentiates phenylalanine metabolism in mice

Yajuan Li, Zhi Tan, Yaohua Zhang, Zhao Zhang, Qingsong Hu, Ke Liang, Yao Jun, Youqiong Ye, Yi Chuan Li, Chunlai Li, Lan Liao, Jianming Xu, Zhen Xing, Yinghong Pan, Sujash S. Chatterjee, Tina K. Nguyen, Heidi Hsiao, Sergey D. Egranov, Nagireddy Putluri, Cristian CoarfaDavid H. Hawke, Preethi H. Gunaratne, Kuang Lei Tsai, Leng Han, Mien Chie Hung, George A. Calin, Fares Namour, Jean Louis Guéant, Ania C. Muntau, Nenad Blau, V. Reid Sutton, Manuel Schiff, François Feillet, Shuxing Zhang, Chunru Lin, Liuqing Yang

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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 PahR408W/R408W mice and improved the Phe tolerance of these mice.

Original languageEnglish (US)
Pages (from-to)662-673
Number of pages12
JournalScience
Volume373
Issue number6555
DOIs
StatePublished - Aug 6 2021

ASJC Scopus subject areas

  • General

MD Anderson CCSG core facilities

  • Genetically Engineered Mouse Facility

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