Objective: To understand the molecular function of a novel missense PINK1 variant identified in an Indian family with Parkinson’s disease (PD).

Background: The molecular understanding of PD is gleaned from discoveries made primarily in the European population and its transferability to other populations is contested. In a scientific collaboration to catalogue the genetic architecture of PD (CAGE-PD) and Genomics Registry of PD (GENOM-PD) in ethnically diverse populations such as the Indian population, we employed exome and genome sequencing in well-characterized PD families from India. We identified a p.Phe385Ser missense mutation in exon 6 in the PINK1 gene in a family from India.

Method: In silico modelling of mutations was performed using the PINK1 structure predicted by AlphaFold2 as well as motif conservation analysis. The functional role of the mutation was assessed by expressing wild-type or F385S PINK1 together with wild-type parkin in HeLa cells that lack endogenous parkin and functional endogenous PINK1¹. The ability of cells to undergo canonical mitophagy was then assessed using quantitative image analysis and biochemical readouts.

Results: The mutation reported in this study has not been observed in any of the databases 1000 Genomes, ExAC or gnomAD. Clinically, the PINK1 mutation carriers had disease-onset at 39 and 27 years, respectively, with typical motor symptoms, including rest tremor, asymmetry and excellent levodopa response that was stable for over a decade, before developing motor fluctuations. Dyskinesia was mild and disease progression was slow. Both developed depression but no other non-motor symptoms. The mutation was within the kinase domain of PINK1 and in silico modelling revealed the mutation to be likely loss of function since it affects the highly conserved DFG motif, which is critical for regulating the kinase domain catalysis as well as ATP binding. Exogenous F385S PINK1 accumulates in cells upon mitochondrial depolarisation but fails to properly engage parkin and inhibits mitochondrial fragmentation, clustering and removal. This is due to the mutation disrupting the kinase function of PINK1 since F385S PINK1 does not phosphorylate ubiquitin.

Conclusion: We identified a novel, population-specific, non-conservative mutation in the DFG motif of PINK1 that is likely detrimental to its kinase activity.

References: 1.Wettengel J, Reautschnig P, Geisler S, Kahle PJ, Stafforst T. Harnessing human ADAR2 for RNA repair – Recoding a PINK1 mutation rescues mitophagy. Nucleic Acids Res. 2017 Mar 17;45(5):2797-808.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-population-specific-pink1-p-f385s-loss-of-function-mutation-in-an-indian-family-with-parkinsons-disease/