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

Publisher: Wiley-Liss Country of Publication: United States NLM ID: 8610688 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1531-8257 (Electronic) Linking ISSN: 08853185 NLM ISO Abbreviation: Mov Disord Subsets: MEDLINE

Publication: <2001->: New York, NY : Wiley-Liss
Original Publication: [New York, N.Y.] : Raven Press, [c1986-

Protein Kinases*/genetics ; Parkinson Disease*/genetics ; Pedigree*; Humans ; India ; Female ; Male ; Middle Aged ; Loss of Function Mutation/genetics ; Adult ; Ubiquitin-Protein Ligases/genetics ; Mutation/genetics ; Exome Sequencing ; Mitophagy/genetics

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 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. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
(© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

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009411 Michael J. Fox Foundation for Parkinson's Research; 023430 Michael J. Fox Foundation for Parkinson's Research; 11879 Michael J. Fox Foundation for Parkinson's Research; 17473 Michael J. Fox Foundation for Parkinson's Research; 654651/GRK2364 Deutsche Forschungsgemeinschaft; SH599/16-1 Deutsche Forschungsgemeinschaft

Keywords: PINK1; Parkinson's disease; genome sequencing; mitophagy; phosphorylation; ubiquitin

EC 2.7.11.1 (PTEN-induced putative kinase)
EC 2.7.- (Protein Kinases)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
EC 2.3.2.27 (parkin protein)

Date Created: 20240408 Date Completed: 20240720 Latest Revision: 20240806

20240806

10.1002/mds.29792

38586902