Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer's disease
| Autor: | Julie Hoogmartens, Elisabeth Hens, Sebastiaan Engelborghs, Rik Vandenberghe, Peter-P. De Deyn, Rita Cacace, Christine Van Broeckhoven, P. Cras, J. Goeman, R. Crols, J.L. De Bleecker, T. Van Langenhove, A. Sieben, B. Dermaut, O. Deryck, B. Bergmans, J. Versijpt |
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| Přispěvatelé: | Neurology, Clinical sciences, Neuroprotection & Neuromodulation, Pathologic Biochemistry and Physiology, BELNEU Consortium, Molecular Neuroscience and Ageing Research (MOLAR) |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Aging Geriatrics & Gerontology Compound heterozygosity Amyloid beta-Protein Precursor 0302 clinical medicine PSEN2 PSEN1 Missense mutation Medicine Genetics Aged 80 and over General Neuroscience Homozygote Alzheimer's disease Middle Aged Chemistry Von Willebrand factor A domain containing 2 gene Female Alzheimer’s disease Life Sciences & Biomedicine Adult Risk Heterozygote Neuroscience(all) Clinical Neurology Mutation Missense Neuropathology Presenilin 03 medical and health sciences Alzheimer Disease Presenilin-2 Biomarkers Tumor Presenilin-1 Humans Allele Biology Aged Homozygous and compound heterozygous missense mutations VWA2 Science & Technology business.industry Haplotype Calcium-Binding Proteins Neurosciences 030104 developmental biology Neurology (clinical) Human medicine Neurosciences & Neurology Geriatrics and Gerontology business 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Neurobiology of aging Neurobiology of Aging, 99, 100.e17-100.e23. ELSEVIER SCIENCE INC |
| ISSN: | 1558-1497 0197-4580 |
| Popis: | Alzheimer's disease is the most frequent diagnosis of neurodegenerative dementia with early (≤65 years) and late (>65 years) onset ages in familial and sporadic patients. Causal mutations in 3 autosomal dominant Alzheimer genes, i.e. amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2), explain only 5%-10% of early-onset patients leaving the majority of patients genetically unresolved. To discover potential missing genetics, we used whole genome sequencing data of 17 early-onset patients with well-documented clinical diagnosis of Alzheimer's disease. In the discovery group, the mean onset age was 55.71 ± 6.83 years (range 37-65). Six patients had a brain autopsy and neuropathology confirmed Alzheimer's disease. Analysis of the genetic data identified in one patient a homozygous p.V366M missense mutation in the Von Willebrand factor A domain containing 2 gene (VWA2). Resequencing of the VWA2 coding region in an Alzheimer's disease patient cohort from Flanders-Belgium (n = 1148), including 152 early and 996 late onset patients, identified additional homozygous and compound heterozygous missense mutations in 1 early and 3 late-onset patients. Allele-sharing analysis identified common haplotypes among the compound heterozygous VWA2 mutation carriers, suggesting shared ancestors. Overall, we identified 5 patient carriers of homozygous or compound heterozygous missense mutations (5/1165; 0.43 %), 2 in early (2/169; 1.18 %) and 3 in late-onset (3/996; 0.30 %) patients. The frequencies of the homozygous and compound heterozygous missense mutations in patients are higher than expected from the frequencies calculated based on their combined single alleles. None of the homozygous/compound heterozygous missense mutation carriers had a family history of autosomal dominant Alzheimer's disease. Our findings suggest that homozygous and compound heterozygous missense mutations in VWA2 might contribute to the risk of Alzheimer's disease in sporadic patients. ispartof: NEUROBIOLOGY OF AGING vol:99 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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