Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition

Abstract

Purpose

Dioxygenases 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.

Methods

We 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.

Results

We 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.

Conclusion

The 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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Fig. 1: Variants in HPDL in eight independent consanguineous families lead to microcephaly and brain atrophy.
Fig. 2: HPD and HPDL display different subcellular localization patterns.
Fig. 3: Hpdl knockout (KO) mice display early lethality, smaller brain sizes, and cellular apoptosis.
Fig. 4: HPD and HPDL evolutionary analysis reveals two separate, yet significant, evolutionary events leading to the emergence of vertebrate HPDL with novel function.

Data availability

Data are available in a public, open access repository. The exome sequencing from individuals from the UCSD study site have been deposited in the Database of Genotypes and Phenotypes under accession numbers phs001272.v1.p1 and phs000744.v4.p2.

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Acknowledgements

The authors thank the patients and their families for participation in this study. This work was supported by NIH U01 MH108898, R01NS048453, R01 NS098004, the Simons Foundation Autism Research Initiative (SFARI), and Qatar National Research Foundation 6–1463 (J.G.G.); NIH S10OD020025 and R01ES027595 (M.J.); the Deutsche Forschungsgemeinschaft (DFG) under Germany´s Excellence Strategy (EXC-2189 project ID: 390939984) and a European Research Council (ERC) Consolidator Grant (648235, N.W.); and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (D.M.). S.G.G. is supported by the Ruth L. Kirschstein Institutional National Research Service Award (T32 GM008666) from the National Institute on Deafness and Other Communication Disorders and by award F31HD095602 from the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development. We thank the Rady Children’s Institute for Genomic Medicine, Broad Institute (U54HG003067 to E. Lander and UM1HG008900 to D. MacArthur), the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and M. Gunel) for sequencing support, and the Matchmaker Exchange. We also thank UCSD Mouse Transgenic Core and UCSD Neuroscience Microscopy Core (P30 NS047101). We acknowledge M. Gerstein, S. Mane, A.B. Ekici, S. Uebe, E.S. Cauley, and UCSD IGM Genetics Center for sequencing support and analysis; the Yale Biomedical High-Performance Computing Center for data analysis and storage; the Yale Program on Neurogenetics; and the Yale Center for Human Genetics. We thank Pradipta Ghosh for sharing CACO-2 cells.

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Correspondence to Joseph G. Gleeson MD.

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Ghosh, S.G., Lee, S., Fabunan, R. et al. Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition. Genet Med (2020). https://doi.org/10.1038/s41436-020-01010-y

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Keywords

  • HPDL
  • HPD
  • 4-hydroxyphenylpyruvate dioxygenase-like protein
  • oxidoreductase
  • neurodegenerative disease

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