Shereen G Ghosh1,2, Sangmoon Lee1,2, Rudy Fabunan3, Guoliang Chai1,2, Maha S Zaki4, Ghada Abdel-Salam4, Tipu Sultan5, Tawfeg Ben-Omran6, Javeria Raza Alvi5, Jennifer McEvoy-Venneri1,2, Valentina Stanley1,2, Aakash Patel1,2, Danica Ross1,2, Jeffrey Ding7, Mohit Jain7, Daqiang Pan8, Philipp Lübbert9, Bernd Kammerer8, Nils Wiedemann9,10, Nanda M Verhoeven-Duif11, Judith J Jans11, David Murphy12, Mehran Beiraghi Toosi13, Farah Ashrafzadeh14, Shima Imannezhad15, Ehsan Ghayoor Karimiani16,17, Khalid Ibrahim18, Elizabeth R Waters3, Reza Maroofian19,20, Joseph G Gleeson21,22. 1. Department of Neurosciences, University of California-San Diego, La Jolla, CA, USA. 2. Rady Children's Institute for Genomic Medicine, San Diego, CA, USA. 3. Biology Department, San Diego State University, San Diego, CA, USA. 4. Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt. 5. Department of Pediatric Neurology, Institute of Child Health, Children Hospital Lahore, Lahore, Pakistan. 6. Division of Genetic and Genomic Medicine, Sidra Medicine and Hamad Medical Corporation, Doha, Qatar. 7. Departments of Medicine and Pharmacology, University of California-San Diego, La Jolla, CA, USA. 8. Centre for Integrative Signalling Analysis (CISA), University of Freiburg, Freiburg, Germany. 9. Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 10. CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany. 11. Section Metabolic Diagnostics, Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 12. Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, Queen Square, London, UK. 13. Pediatric Neurology Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. 14. Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 15. Department of Pediatric Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 16. Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London, UK. 17. Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran. 18. Division of Pediatric Neurology, Sidra Medicine, Doha, Qatar. 19. Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's University, London, UK. 20. Department of Neuromuscular Disorders, UCL Institute of Neurology, Queen Square, London, UK. 21. Department of Neurosciences, University of California-San Diego, La Jolla, CA, USA. jogleeson@health.ucsd.edu. 22. Rady Children's Institute for Genomic Medicine, San Diego, CA, USA. jogleeson@health.ucsd.edu.
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.
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.
Authors: Robert S Banh; Esther S Kim; Quentin Spillier; Douglas E Biancur; Keisuke Yamamoto; Albert S W Sohn; Guangbin Shi; Drew R Jones; Alec C Kimmelman; Michael E Pacold Journal: Nature Date: 2021-09-01 Impact factor: 69.504