Genotype-phenotype correlation in PRKN-associated Parkinson's disease
Menon, Poornima Jayadev (Royal College of Surgeons in Ireland)
Sambin, Sara (Hôpital Pitié-Salpêtière (París, França))
Criniere-Boizet, Baptiste (Sorbonne Université)
Courtin, Thomas (Hôpital Pitié-Salpêtière (París, França))
Tesson, Christelle (Sorbonne Université)
Casse, Fanny (Sorbonne Université)
Ferrien, Melanie (Sorbonne Université)
Mariani, Louise-Laure (Hôpital Pitié-Salpêtière (París, França))
Carvalho, Stephanie (Sorbonne Université)
Lejeune, Francois-Xavier (Sorbonne Université)
Rebbah, Sana (Sorbonne Université)
Martet, Gaspard (Sorbonne Université)
Houot, Marion (Hospital de la Pitié-Salpêtrière (París, França))
Lanore, Aymeric (Hôpital Pitié-Salpêtière (París, França))
Mangone, Graziella (Rush University Medical Center)
Roze, Emmanuel (Hôpital Pitié-Salpêtière (París, França))
Vidailhet, Marie (Hôpital Pitié-Salpêtière (París, França))
Aasly, Jan O. (Norwegian University of Science and Technology)
Gan Or, Ziv (McGill University)
Yu, Eric (McGill University)
Dauvilliers, Yves (University of Montpellier)
Zimprich, Alexander (University Hospital Vienna)
Tomantschger, Volker (Gailtal-Klinik Hermagor)
Pirker, Walter (Ottakring Clinic)
Alvarez, Ignacio (Universitat de Barcelona. Hospital Mútua de Terrassa)
Pastor, Pau (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Di Fonzo, Alessio (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milà, Itàlia))
Bhatia, Kailash P. (University College London)
Magrinelli, Francesca (University College London)
Houlden, Henry (UCL Institute of Neurology (Regne Unit))
Real, Raquel (Aligning Science Across Parkinson's Collaborative Research Network)
Quattrone, Andrea (Magna Graecia University of Catanzaro)
Limousin, Patricia (University College London)
Korlipara, Prasad (University College London)
Foltynie, Thomas (University College London)
Grosset, Donald (University of Glasgow)
Williams, Nigel (Cardiff University)
Narendra, Derek (National Institutes of Health (Estats Units d'Amèrica))
Lin, Hsin-Pin (National Institutes of Health (Estats Units d'Amèrica))
Jovanovic, Carna (University Clinical Center of Serbia)
Svetel, Marina (University Clinical Center of Serbia)
Lynch, Timothy (University College Dublin)
Gallagher, Amy (University College Dublin)
Vandenberghe, Wim (University Hospitals Leuven (Bèlgica))
Gasser, Thomas (German Center for Neurodegenerative Diseases (DZNE))
Brockmann, Kathrin (German Center for Neurodegenerative Diseases (DZNE))
Morris, Huw (University College London)
Borsche, Max (University of Lübeck (Alemanya))
Klein, Christine (University of Lübeck (Alemanya))
Corti, Olga (Sorbonne Université)
Brice, Alexis (Hôpital Pitié-Salpêtière (París, França))
Lesage, Suzanne (Sorbonne Université)
Corvol, Jean Christophe Corvol (Hôpital Pitié-Salpêtière (París, França))

Data:	2024
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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	NPJ Parkinson's disease, Vol. 10 Núm. 1 (december 2024) , p. 72, ISSN 2373-8057

DOI: 10.1038/s41531-024-00677-3
PMID: 38553467

12 p, 2.5 MB

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