NOVEL AND KNOWN RARE SORL1 MUTATIONS IN KOREAN AD PATIENTS

Abstract

Even though APP, PSEN1 and PSEN2 are major causative genes for Alzheimer's disease (AD), they are relatively rare. We are perusing to find other novel genes in the disease progression. Since SORL1 gene was suggested in playing a protective role against amyloid beta secretion, mutation in SORL1 could be involved in the disease progression. We performed a complex genetic screening by NGS for 50 genes, including SORL1 gene. NGS data was confirmed by standard sequencing. We performed PolyPhen2, SIFT and 3D protein structure prediction for the rare mutations. We found several rare probable novel SORL1variants, such as V277I, G511R, D862E, R1159Q, T1483A, G1524R and V2097I. We also detected the common A528T mutation among our patients. Most of them were predicted as possible damaging from the predictions. It is too early to say that these mutations in SORL1 could be involved in disease progression. Mutations in SORL1 may be involved in loss-of-function mechanisms. Previous segregation analyses revealed that rare SORL1 mutations could be also associated with early onset familial AD.