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

Shereen G Ghosh1,2, Sangmoon Lee1,2, Rudy Fabunan3

  • 1Department of Neurosciences, University of California-San Diego, La Jolla, CA, USA.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
|November 14, 2020
PubMed

Insights

Genetic variants in the 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) gene cause a rare mitochondrial infantile neurodegenerative disease. This discovery links HPDL to a novel neurometabolic disorder.

Area of Science:

  • Biochemistry
  • Genetics
  • Neuroscience

Background:

  • Dioxygenases are crucial oxidoreductase enzymes for aerobic metabolism.
  • 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) is an orphan paralogue of 4-hydroxyphenylpyruvate dioxygenase (HPD).
  • The function of HPDL and its role in human diseases were previously unknown.

Purpose of the Study:

  • To investigate the function of HPDL and its potential association with human diseases.
  • To explore the evolutionary relationship between HPDL and HPD.

Main Methods:

  • Exome sequencing in over 10,000 individuals with neurodevelopmental diseases.
  • In vitro and in vivo studies of HPDL loss-of-function effects.
  • Mass spectrometry and evolutionary analyses.

Main Results:

  • Biallelic HPDL variants were identified in eight families with recessive inheritance.
  • HPDL knockout mice models recapitulated human phenotypes, showing cerebral cortex apoptosis.
  • HPDL is a mitochondria-localized, single-exonic gene, distinct from HPD, with altered metabolic profiles in mutants.

Conclusions:

  • HPDL loss is linked to a novel mitochondrial infantile neurodegenerative condition.
  • Mitochondrial localization and disrupted metabolic pathways are key features of HPDL-related disease.
  • This study elucidates the function of HPDL and its implication in human pathology.
Abstract

Keywords:
4-hydroxyphenylpyruvate dioxygenase-like proteinHPDHPDLneurodegenerative diseaseoxidoreductase

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