biostudies-literatureLi YThe University of Texas MD Anderson Cancer CenterU.S. Department of DefenseNational Cancer InstituteNCI NIH HHSNational Institutes of HealthNational Research University FundCancer Prevention and Research Institute of TexasAmerican Association for Cancer ResearchNIH HHSNational Science FoundationAndrew Sabin Family Foundation662-673https://www.ebi.ac.uk/biostudies/studies/S-EPMC9714245biostudies-literatureUnknown373(6555)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 Science (New York, N.Y.)A noncoding RNA modulator potentiates phenylalanine metabolism in mice.PMC9714245S10 OD012304CA218025-01P30CA125123R01 CA218036180259RP170333R01 CA231011CHE-1411859MINOR CORE 17CA218036-01R01 CA220297R01CA225955BC180196BC181384RP200423R01 CA218025RP170005R01 CA216426CA231011-01P30 CA125123RP150085RP1905702018P30 CA01667220-60-51 Yang1S10OD012304-01R01 CA225955Institutional Research GrantGunaratne PHHan LHsiao HYe YZhang SPutluri NLiao LNamour FJun YTsai KLFeillet FLiang KNguyen TKXing ZPan YLi CYang LCoarfa CSchiff MMuntau ACXu JGueant JLLi YLi YCEgranov SDBlau NLin CZhang ZHung MCTan ZZhang YSutton VRCalin GAHawke DHHu QChatterjee SSfalseA 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 <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 2021-01-01T00:00:00Z2021 Aug2026-05-28T21:29:03.929Z2025-04-19T22:49:56.466ZS-EPMC97142453435394910.1126/science.aba4991