ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05848271 (A Patient Registry and Natural History Study of Patients with Biallelic HPDL Mutations), which is not on this map. Cited by 23 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Patient Registry and Natural History Study of Patients with Biallelic HPDL Mutations
Who cites it
23 citing papers in PubMed, 36 citations in OpenAlex.
- Loss of function variants in HPDL impair human cortical development via alterations of mitochondrial function.Cell death & disease · 2026Article
- Mitochondrial Dysfunctions in Human Primary Coenzyme QBiomolecules · 2026Review
- Regulation of Histone Emulsification by HPDL via LDHA/LDHB Promotes EC Cell Proliferation.Oncology research · 2026Article
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- HPDL Variant Type Correlates With Clinical Disease Onset and Severity.Annals of clinical and translational neurology · 2025Observational
- Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Neurodevelopmental Implications Underpinning Hereditary Spastic Paraplegia.CNS neuroscience & therapeutics · 2025Review
- Generation and Characterization of hiPS Lines from Three Patients Affected by Different Forms ofInternational journal of molecular sciences · 2024Article
- Inhibition of BCAT1-mediated cytosolic leucine metabolism regulates Th17 responses via the mTORC1-HIF1α pathway.Experimental & molecular medicine · 2024Article
- A novel homozygous HPDL variant in Japanese siblings with autosomal recessive hereditary spastic paraplegia: case report and literature review.Neurogenetics · 2024Review
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- Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias.International journal of molecular sciences · 2024Review
- Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism.PLoS biology · 2024Article
- Transcriptome analysis reveals effects of ethynylestradiol and bisphenol A on multiple endocrine and metabolic pathways in the pituitary and liver of female Atlantic cod (Frontiers in endocrinology · 2024Article
- Neuroimaging in Primary Coenzyme-QAntioxidants (Basel, Switzerland) · 2023Review
- The Human Glyoxalase Gene Family in Health and Disease.Chemical research in toxicology · 2022Review
- HPDL mutations identified by exome sequencing are associated with infant neurodevelopmental disorders.Molecular genetics & genomic medicine · 2022Article
- Case Report: Two Families WithFrontiers in genetics · 2022Article
Corrections and comments
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Authors and funding
30 authors at 10 institutions in 7 countries.
Funding
Abstract
purposeDioxygenases are oxidoreductase enzymes with roles in metabolic pathways necessary for aerobic life. 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), encoded by HPDL, is an orphan paralogue of 4-hydroxyphenylpyruvate dioxygenase (HPD), an iron-dependent dioxygenase involved in tyrosine catabolism. The function and association of HPDL with human diseases remain unknown.
methodsWe applied exome sequencing in a cohort of over 10,000 individuals with neurodevelopmental diseases. Effects of HPDL loss were investigated in vitro and in vivo, and through mass spectrometry analysis. Evolutionary analysis was performed to investigate the potential functional separation of HPDL from HPD.
resultsWe identified biallelic variants in HPDL in eight families displaying recessive inheritance. Knockout mice closely phenocopied humans and showed evidence of apoptosis in multiple cellular lineages within the cerebral cortex. HPDL is a single-exonic gene that likely arose from a retrotransposition event at the base of the tetrapod lineage, and unlike HPD, HPDL is mitochondria-localized. Metabolic profiling of HPDL mutant cells and mice showed no evidence of altered tyrosine metabolites, but rather notable accumulations in other metabolic pathways.
conclusionThe mitochondrial localization, along with its disrupted metabolic profile, suggests HPDL loss in humans links to a unique neurometabolic mitochondrial infantile neurodegenerative condition.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.