A Functional Genetic Atlas of Parkin Resolves Variants of Uncertain Significance and Predicts Parkinson's Disease Age at Onset
Aslanzadeh, V.; Glendinning, S.; Sari, Y.; Clarke, M.; Rodger, C. J.; Lin, X.; Lenka, D. R.; Richardson, L.; Liang, J. R.; Kleinz, T.; Sproul, D.; Lohmann, K.; Klein, C.; Sammler, E. M.; Alessi, D. R.; Kumar, A.; Muqit, M. M.; Kudla, G.
Show abstract
Autosomal recessive mutations in the Parkin gene (PRKN) cause early-onset Parkinsons disease (PD). Parkin functions as a ubiquitin E3 ligase acting downstream of the PINK1 kinase to promote phosphorylated ubiquitin at sites of mitochondrial damage. Yet the functional effects of most PRKN gene variants remain unknown. Here we use a pooled cellular assay measuring phosphorylated ubiquitin accumulation to quantify the activity of [~]9,200 PRKN missense and nonsense variants. Our screen identifies thousands of loss- and gain-of-function variants, including activating variants mainly residing at autoinhibitory interfaces. Functional scores accurately distinguish known PD pathogenic and benign variants, and enable reclassification of 173/184 variants of uncertain significance (VUS). When combined into biallelic genotype scores, these data predict the age at disease onset in patients, revealing a quantitative link between Parkin activity and clinical manifestation. Our results provide a comprehensive functional genetic map of Parkin and demonstrate the power of multiplexed assays of variant effects (MAVEs) for variant interpretation and precision medicine in PD.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- A mutational atlas for Parkin proteostasis 97%
- CRISPR/Cas9-Mediated Excision of ALS/FTD-Causing Hexanucleotide Repeat Expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro 94%
- Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies 94%
Similar papers in this journal
- An engineered transcriptional reporter of protein localization identifies regulators of mitochondrial and ER membrane protein trafficking in high-throughput screens 93%
- Maintenance of neuronal TDP-43 expression requires axonal lysosome transport 93%
- Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders 93%
Similar papers in this journal
- Landscapes of missense variant impact for human superoxide dismutase 1 92%
- Loss of C2orf69 defines a fatal auto-inflammatory mitochondriopathy in Humans and Zebrafish 92%
- High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency 92%
Similar papers in this journal
- Genomic analyses of glycine decarboxylase neurogenic mutations yield a large scale prediction model for prenatal disease. 94%
- Disentangling the mutational effects on protein stability and interaction of human MLH1 93%
- DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.