TY - JOUR
T1 - Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition
AU - Ghosh, Shereen G
AU - Lee, Sangmoon
AU - Fabunan, Rudy
AU - Chai, Guoliang
AU - Zaki, Maha S
AU - Abdel-Salam, Ghada
AU - Sultan, Tipu
AU - Ben-Omran, Tawfeg
AU - Alvi, Javeria Raza
AU - McEvoy-Venneri, Jennifer
AU - Stanley, Valentina
AU - Patel, Aakash
AU - Ross, Danica
AU - Ding, Jeffrey
AU - Jain, Mohit
AU - Pan, Daqiang
AU - Lübbert, Philipp
AU - Kammerer, Bernd
AU - Wiedemann, Nils
AU - Verhoeven-Duif, Nanda M
AU - Jans, Judith J
AU - Murphy, David
AU - Toosi, Mehran Beiraghi
AU - Ashrafzadeh, Farah
AU - Imannezhad, Shima
AU - Karimiani, Ehsan Ghayoor
AU - Ibrahim, Khalid
AU - Waters, Elizabeth R
AU - Maroofian, Reza
AU - Gleeson, Joseph G
N1 - Funding Information:
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.
Publisher Copyright:
© 2020, American College of Medical Genetics and Genomics.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - 4-hydroxyphenylpyruvate dioxygenase-like protein
KW - HPD
KW - HPDL
KW - neurodegenerative disease
KW - oxidoreductase
UR - https://www.scopus.com/pages/publications/85095884454
U2 - 10.1038/s41436-020-01010-y
DO - 10.1038/s41436-020-01010-y
M3 - Article
C2 - 33188300
SN - 1098-3600
VL - 23
SP - 524
EP - 533
JO - Genetics in medicine : official journal of the American College of Medical Genetics
JF - Genetics in medicine : official journal of the American College of Medical Genetics
IS - 3
ER -