A Novel PINK1 p.F385S Loss-of-Function Mutation in an Indian Family with Parkinson's Disease

Karan Sharma, Asha Kishore, Anna Lechado-Terradas, Raffaele Passannanti, Francesco Raimondi, Marc Sturm, Ashwin Ashok Kumar Sreelatha, Divya Kalikavila Puthenveedu, Gangadhara Sarma, Nicolas Casadei, Rejko Krüger, Thomas Gasser, Philipp Kahle, Olaf Riess, Julia C. Fitzgerald, Manu Sharma*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research. Objective: The aim of this study was to characterize a novel phosphatase tensin homolog-induced serine/threonine kinase 1 (PINK1) mutation causing PD in an Indian family. Methods: Exome sequencing of a well-characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment. Results: We identified a homozygous chr1:20648535–20648535 T>C on GRCh38 (p.F385S) mutation in exon 6 of PINK1, which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved Deutsche Forschungsgemeinschaft (DFG) motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization. Conclusions: We characterized a novel nonconservative mutation in the DFG motif of PINK1, which causes loss of its ubiquitin kinase activity and inhibition of mitophagy.

Original languageEnglish
JournalMovement Disorders
Early online date8 Apr 2024
DOIs
Publication statusE-pub ahead of print - 8 Apr 2024

Keywords

  • genome sequencing
  • mitophagy
  • Parkinson's disease
  • phosphorylation
  • PINK1
  • ubiquitin

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