Genotype-phenotype correlation in PRKN-associated Parkinson's disease

Walter Pirker, Max Borsche, Olga Corti, Carna Jovanovic, Louise-Laure Mariani, Baptiste Criniere-Boizet, Ignacio Alvarez, Melanie Ferrien, Henry Houlden, Francesca Magrinelli, Fanny Casse, Kailash P. Bhatia, Volker Tomantschger, Pau Pastor, Alexis Brice, Prasad Korlipara, Alessio Di Fonzo, Gaspard Martet, Nigel Williams, Ziv Gan OrTimothy Lynch, Hsin-Pin Lin, Raquel Real, Emmanuel Roze, Huw Morris, Marion Houot, Marie Vidailhet, Amy Gallagher, Derek Narendra, Graziella Mangone, Eric Yu, Suzanne Lesage, Thomas Courtin, Aymeric Lanore, Jan O Aasly, Thomas Foltynie, Marina. Svetel, Patricia Limousin, Christelle Tesson, Alexander Zimprich, Yves Dauvilliers, Sana Rebbah, Christine Klein, Jean Christophe Corvol Corvol, Andrea Quattrone, Stephanie Carvalho, Wim Vandenberghe, Sara Sambin, Donald Grosset, Kathrin Brockmann, Poornima Jayadev Menon, Thomas Gasser, Francois-Xavier Lejeune

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Resum

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson's disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.
Idioma originalAnglès
Número d’article72
Nombre de pàgines12
Revistanpj Parkinson's Disease
Volum10
Número1
DOIs
Estat de la publicacióPublicada - 29 de març 2024

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