A noncoding RNA modulator potentiates phenylalanine metabolism in mice.
basic_science · Level V
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- Record sourced from PubMed, PMID 34353949.
- Also identified by DOI 10.1126/science.aba4991 and PMC identifier 9714245.
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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 <i>Pair</i> and human <i>HULC</i> associate with phenylalanine hydroxylase (PAH). <i>Pair</i>-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. <i>HULC</i> depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically, <i>HULC</i> 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-<i>HULC</i> mimics reduced excessive Phe in <i>Pair</i> <sup>-/-</sup> and <i>Pah</i> <sup>R408W/R408W</sup> mice and improved the Phe tolerance of these mice.
Medical subject headings
- Phenylalanine
- Phenylalanine Hydroxylase
- Phenylketonurias
- RNA, Long Noncoding