A5092478580- Genomics and Rare Diseases
- Alzheimer's disease research and treatments
- Bioinformatics and Genomic Networks
- Biochemical and Structural Characterization
- Machine Learning in Bioinformatics
- Biomedical Text Mining and Ontologies
- Mitochondrial Function and Pathology
Amsterdam University Medical Centers
2023-2024
Amsterdam Neuroscience
2023
Vrije Universiteit Amsterdam
2023
Abstract Background Protein truncating variants (PTVs) in SORL1 are observed almost exclusively Alzheimer’s Disease (AD) cases, but the effect of rare missense is unclear. Methods To identify high-priority (HPVs), we applied ‘domain mapping disease mutations’ on 637 unique coding detected 18,959 AD-cases and 21,893 non-demented controls. Results In this sample, PTVs HPVs associated with respectively a 35- 10-fold increased risk early onset AD 17- 6-fold overall AD. The median age at (AAO)...
Abstract Background SORL1 encodes the retromer‐associated receptor SORLA that functions in endosomal recycling. Rare variants have been associated with Alzheimer’s disease (AD) and rare pathogenic are estimated to occur up 2.75% of early onset AD patients 1.5% unrelated late patients. While truncation mutations observed almost exclusively patients, it is currently unknown which among hundreds missense identified , pathogenic. Method Here we address this question by relying on SORLA’s...
Abstract Background The sortilin‐related receptor 1 protein, SORL1, interacts with retromer to regulate trafficking of cargo out the early endosome. Genetic variants in SORL1 that lead a premature protein truncation (PTVs) are observed almost exclusively Alzheimer’s disease (AD) patients, suggesting ’s haploinsufficiency may be causal for AD. However, large majority rare missense which affect diverse structural domains, some causative or (strongly) risk‐increasing, while others (likely)...
Abstract Background Rare pathogenic SORL1 gene variants have been identified as strong risk‐increasing factors in Alzheimer’s disease (AD). Recent analysis indicated that loss‐of‐function (LoF) associated with a ∼40‐fold increased risk for early‐onset AD, while missense were prioritized using silico variant pathogenicity‐prediction algorithms only 2‐fold increase. However, current risk‐prediction strategies do not take SORL1‐specific features into account. We aimed to design classification...