ArticleNature communications2021
The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 26 citations in OpenAlex.
- Overweight and obesity in adult patients with phenylketonuria: a systematic review.Orphanet journal of rare diseases · 2023Pooled it
- DNAJC12 Stabilizes Phenylalanine Hydroxylase and Facilitates Its Substrate-Dependent Activation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- THBS4 Regulates Pulmonary Hypertension via TGF-β/SMAD2 Signaling.Hypertension (Dallas, Tex. : 1979) · 2026Article
- Base editing strategies forMolecular therapy. Nucleic acids · 2025Article
- Advancing Gene Therapy for Phenylketonuria: From Precision Editing to Clinical Translation.International journal of molecular sciences · 2025Review
- Experimental Animal Models of Phenylketonuria: Pros and Cons.International journal of molecular sciences · 2025Review
- Phenotypic study of humanized mice carrying the PAH deep intronic variant c.1199+502A>T.Orphanet journal of rare diseases · 2025Article
- PAH deficient pathology in humanized c.1066-11G>A phenylketonuria mice.Human molecular genetics · 2024Article
- ifDEEPre: large protein language-based deep learning enables interpretable and fast predictions of enzyme commission numbers.Briefings in bioinformatics · 2024Article
- State-of-the-art 2023 on gene therapy for phenylketonuria.Journal of inherited metabolic disease · 2024Review
- Deubiquitinase USP19 enhances phenylalanine hydroxylase protein stability and its enzymatic activity.Cell biology and toxicology · 2023Article
- Deubiquitinase USP19 extends the residual enzymatic activity of phenylalanine hydroxylase variants.Scientific reports · 2022Article
- Article
- Isolation, identification, and characterization of corn-derived antioxidant peptides from corn fermented milk byFrontiers in nutrition · 2022Article
- Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia-A Focus on Tyrosine Hydroxylase Deficiency.Journal of personalized medicine · 2021Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Phenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A homozygous Pah-R261Q mouse, with a highly prevalent misfolding variant in humans, reveals the expected hepatic PAH activity decrease, systemic L-Phe increase, L-tyrosine and L-tryptophan decrease, and tetrahydrobiopterin-responsive hyperphenylalaninemia. Pah-R261Q mice also present unexpected traits, including altered lipid metabolism, reduction of liver tetrahydrobiopterin content, and a metabolic profile indicative of oxidative stress. Pah-R261Q hepatic tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates of mutant PAH that colocalize with selective autophagy markers. Together, these findings reveal that PKU, customarily considered a loss-of-function disorder, can also have toxic gain-of-function contribution from protein misfolding and aggregation. The proteostasis defect and concomitant oxidative stress may explain the prevalence of comorbid conditions in adult PKU patients, placing this mouse model in an advantageous position for the discovery of mutation-specific biomarkers and therapies.
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