한빛사 논문
Shereen G. Ghosh MSc, Sangmoon Lee MD, PhD, Rudy Fabunan MS, Guoliang Chai PhD, Maha S. Zaki MD, PhD, Ghada Abdel-Salam PhD, Tipu Sultan MSc, FRCPCH, Tawfeg Ben-Omran MD, FRCPS, Javeria Raza Alvi MBBS, FCPS, Jennifer McEvoy-Venneri BS, Valentina Stanley BS, Aakash Patel BS, Danica Ross BS, Jeffrey Ding BS, Mohit Jain MD, PhD, Daqiang Pan PhD, Philipp Lübbert PhD, Bernd Kammerer PhD, Nils Wiedemann PhD, Nanda M. Verhoeven-Duif PhD, Judith J. Jans PhD, David Murphy MSc, Mehran Beiraghi Toosi MD, Farah Ashrafzadeh MD, Shima Imannezhad MD, Ehsan Ghayoor Karimiani MD, PhD, Khalid Ibrahim MD, FRCPCH, Elizabeth R. Waters PhD, Reza Maroofian PhD & Joseph G. Gleeson MD*
These authors contributed equally: Shereen G. Ghosh, Sangmoon Lee.
*Corresponding author
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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