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

Shereen G Ghosh, Sangmoon Lee, Rudy Fabunan, Guoliang Chai, Maha S Zaki, Ghada Abdel-Salam, Tipu Sultan, Tawfeg Ben-Omran, Javeria Raza Alvi, Jennifer McEvoy-Venneri, Valentina Stanley, Aakash Patel, Danica Ross, Jeffrey Ding, Mohit Jain, Daqiang Pan, Philipp Lübbert, Bernd Kammerer, Nils Wiedemann, Nanda M Verhoeven-Duif, Judith J Jans, David Murphy, Mehran Beiraghi Toosi, Farah Ashrafzadeh, Shima Imannezhad, Ehsan Ghayoor Karimiani, Khalid Ibrahim, Elizabeth R Waters, Reza Maroofian, Joseph G Gleeson, Shereen G Ghosh, Sangmoon Lee, Rudy Fabunan, Guoliang Chai, Maha S Zaki, Ghada Abdel-Salam, Tipu Sultan, Tawfeg Ben-Omran, Javeria Raza Alvi, Jennifer McEvoy-Venneri, Valentina Stanley, Aakash Patel, Danica Ross, Jeffrey Ding, Mohit Jain, Daqiang Pan, Philipp Lübbert, Bernd Kammerer, Nils Wiedemann, Nanda M Verhoeven-Duif, Judith J Jans, David Murphy, Mehran Beiraghi Toosi, Farah Ashrafzadeh, Shima Imannezhad, Ehsan Ghayoor Karimiani, Khalid Ibrahim, Elizabeth R Waters, Reza Maroofian, Joseph G Gleeson

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.

Keywords: 4-hydroxyphenylpyruvate dioxygenase-like protein; HPD; HPDL; neurodegenerative disease; oxidoreductase.

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