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

doi:10.1038/s41436-020-01010-y

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

Genet Med. 2021 Mar;23(3):524-533. doi: 10.1038/s41436-020-01010-y. Epub 2020 Nov 14.

Authors

Shereen G Ghosh^#^{1

2}, Sangmoon Lee^#^{1

2}, Rudy Fabunan³, Guoliang Chai^{1

2}, Maha S Zaki⁴, Ghada Abdel-Salam⁴, Tipu Sultan⁵, Tawfeg Ben-Omran⁶, Javeria Raza Alvi⁵, Jennifer McEvoy-Venneri^{1

2}, Valentina Stanley^{1

2}, Aakash Patel^{1

2}, Danica Ross^{1

2}, Jeffrey Ding⁷, Mohit Jain⁷, Daqiang Pan⁸, Philipp Lübbert⁹, Bernd Kammerer⁸, Nils Wiedemann^{9

10}, Nanda M Verhoeven-Duif¹¹, Judith J Jans¹¹, David Murphy¹², Mehran Beiraghi Toosi¹³, Farah Ashrafzadeh¹⁴, Shima Imannezhad¹⁵, Ehsan Ghayoor Karimiani^{16

17}, Khalid Ibrahim¹⁸, Elizabeth R Waters³, Reza Maroofian^{19

20}, Joseph G Gleeson^{21

22}

Affiliations

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. [email protected].
²² Rady Children's Institute for Genomic Medicine, San Diego, CA, USA. [email protected].

^# Contributed equally.

PMID: 33188300
DOI: 10.1038/s41436-020-01010-y

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

4-Hydroxyphenylpyruvate Dioxygenase* / genetics
Animals
Dioxygenases*
Exons
Humans
Mice
Mice, Knockout
Phenotype

Substances

Dioxygenases
4-Hydroxyphenylpyruvate Dioxygenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding