@article {916, title = {Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 03}, pages = {524-533}, 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, Animals, Dioxygenases, Exons, Mice, Mice, Knockout, Phenotype}, issn = {1530-0366}, doi = {10.1038/s41436-020-01010-y}, author = {Ghosh, Shereen G and Lee, Sangmoon and Fabunan, Rudy and Chai, Guoliang and Zaki, MAH S and Abdel-Salam, Ghada and Sultan, Tipu and Ben-Omran, Tawfeg and Alvi, Javeria Raza and McEvoy-Venneri, Jennifer and Stanley, Valentina and Patel, Aakash and Ross, Danica and Ding, Jeffrey and Jain, Mohit and Pan, Daqiang and L{\"u}bbert, Philipp and Kammerer, Bernd and Wiedemann, Nils and Verhoeven-Duif, Nanda M and Jans, Judith J and Murphy, David and Toosi, Mehran Beiraghi and Ashrafzadeh, Farah and Imannezhad, Shima and Karimiani, Ehsan Ghayoor and Ibrahim, Khalid and Waters, Elizabeth R and Maroofian, Reza and Gleeson, Joseph G} }