Truncating genetic variants of SORL1, encoding the endosome recycling receptor SORLA, have been accepted as causal of Alzheimer's disease (AD). However, most genetic variants observed in SORL1 are missense variants, for which it is complicated to determine the pathogenicity level because carriers come from pedigrees too small to be informative for penetrance estimations. Here, we describe three unrelated families in which the SORL1 coding missense variant rs772677709, that leads to a p.Y1816C substitution, segregates with Alzheimer's disease. Further, we investigate the effect of SORLA p.Y1816C on receptor maturation, cellular localization, and trafficking in cell-based assays. Under physiological circumstances, SORLA dimerizes within the endosome, allowing retromer-dependent trafficking from the endosome to the cell surface, where the luminal part is shed into the extracellular space (sSORLA). Our results showed that the p.Y1816C mutant impairs SORLA homodimerization in the endosome, leading to decreased trafficking to the cell surface and less sSORLA shedding. These trafficking defects of the mutant receptor can be rescued by the expression of the SORLA 3Fn-minireceptor. Finally, we find that iPSC-derived neurons with the engineered p.Y1816C mutation have enlarged endosomes, a defining cytopathology of AD. Our studies provide genetic as well as functional evidence that the SORL1 p.Y1816C variant is causal for AD. The partial penetrance of the mutation suggests this mutation should be considered in clinical genetic screening of multiplex early-onset AD families.

Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam University Medical Center 1081 HV Amsterdam The Netherlands

Ann Romney Center for Neurologic Diseases Harvard Medical School and Brigham and Women's Hospital Boston MA 02115

Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas CIBERNED 28029 Madrid Spain

Complex Genetics of Alzheimer's Disease Group Vlaams Instituut voor Biotechnologie Center for Molecular Neurology VIB 2000 Antwerp Belgium

Department of Biomedical Sciences University of Antwerp 2000 Antwerp Belgium

Department of Biomedicine Aarhus University Aarhus C DK8000 Denmark

Department of Histology and Embryology Faculty of Medicine Brno 62500 Czech Republic

Institut d'Investigacions Biomèdiques Sant Pau Hospital de Sant Pau Universitat Autònoma de Barcelona 08041 Barcelona Spain

International Clinical Research Center St Anne's Faculty Hospital Brno 60200 Brno Czech Republic

Memory Unit Department of Neurology Institut d'Investigacions Biomèdiques Sant Pau Hospital de Sant Pau Universitat Autònoma de Barcelona 08025 Barcelona Spain

Molecular Markers Laboratory Instituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli 25125 Brescia Italy

Neurodegenerative Brain Diseases Group VIB Center for Molecular Neurology VIB 2000 Antwerp Belgium

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