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Molecular neurodegeneration · 2025

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Andersen Olav M, de Waal Matthijs W J, Monti Giulia, Tesi Niccolo, Jensen Anne Mette G, de Geus Christa, van Spaendonk Rosalina, Vogel Maartje, Ahmad Shahzad, Amin Najaf, Amouyel Philippe, Beecham Gary W, Bellenguez Céline, Berr Claudine, Bis Joshua C, Boland Anne, Bossù Paola, Bouwman Femke, Bras Jose, Charbonnier Camille, Clarimon Jordi, Cruchaga Carlos, Daniele Antonio, Dartigues Jean-François, Debette Stéphanie, Deleuze Jean-François, Denning Nicola, DeStefano Anita L, Dols-Icardo Oriol, van Duijn Cornelia M, Farrer Lindsay A, Fernández Maria Victoria, van der Flier Wiesje M, Fox Nick C, Galimberti Daniela, Genin Emmanuelle, Gille Johan J P, Grenier-Boley Benjamin, Grozeva Detelina, Guen Yann Le, Guerreiro Rita, Haines Jonathan L, Holmes Clive, Hummerich Holger, Arfan Ikram M, Kamran Ikram M, Kawalia Amit, Kraaij Robert, Lambert Jean-Charles, Lathrop Marc, Lemstra Afina W, Lleó Alberto, Myers Richard M, Mannens Marcel M A M, Marshall Rachel, Martin Eden R, Masullo Carlo, Mayeux Richard, Mead Simon, Mecocci Patrizia, Meggy Alun, Mol Merel O, Nacmias Benedetta, Naj Adam C, Napolioni Valerio, Nicholas Cochran J, Nicolas Gaël, Pasquier Florence, Pastor Pau, Pericak-Vance Margaret A, Pijnenburg Yolande A L, Piras Fabrizio, Quenez Olivier, Ramirez Alfredo, Raybould Rachel, Redon Richard, Reinders Marcel J T, Richard Anne-Claire, Riedel-Heller Steffi G, Rivadeneira Fernando, van Rooij Jeroen G J, Rousseau Stéphane, Ryan Natalie S, Sanchez-Juan Pascual, Schellenberg Gerard D, Scheltens Philip, Schott Jonathan M, Seshadri Sudha, Sie Daoud, Sims Rebecca, Sistermans Erik A, Sorbi Sandro, van Swieten John C, Tijms Betty, Uitterlinden André G, Visser Pieter Jelle, Wagner Michael, Wallon David, Wang Li-San, Williams Julie, Yokoyama Jennifer S, Zarea Aline, van der Lee Sven J, Olsen Johan G, Hulsman Marc, Holstege Henne

Аннотация

BACKGROUND: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. METHODS: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. RESULTS: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. CONCLUSION: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Предметные рубрики MeSH

ИП Урсолов Владлен Сергеевич

ИНН 500118482352 · ОГРНИП 314500117700049

Реквизиты и контакты