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P1–074: A systematic analysis of genomic changes in Tg2576 mice
Author(s) -
Tan Lu
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.05.295
Subject(s) - microarray analysis techniques , gene , biology , microarray , gene expression , false discovery rate , bioconductor , gene expression profiling , computational biology , dna microarray , fold change , significance analysis of microarrays , genetics , bioinformatics
Background: Mutations associated with familial early-onset Alzheimer’s disease (AD) were typically found in amyloid precursor protein (APP), and presenilin1 (PSEN1) and presenilin2 (PSEN2). Among them, mutations in PSEN2 are rare, and fewer than 30 different PSEN2 mutations were reported.Methods: 89 dementia patients under 60 years of age were screened for AD mutations. A PCR based genetic analysis was performed on above dementia patients and 128 normal controls. Following segments were amplified: the APP exon 16-17; PSEN1 exon 4-8 and 11; PSEN2 exon 4-7 and 12. Two efficient mutation detection methods were used for screening our samples: single strand conformation polymorphism (SSCP) and heteroduplex analysis with mismatch-specific nuclease. For the identification and confirmation of the specific mutations, the PCR products were sequenced. Results: A missense PSEN2 mutation, a Val->Leu exchange at codon 214, was found in two unrelated patients. Val214Leu is located at the IVth transmembrane domain of presenilin 2 (PS2). PSEN2Val214Leuwas screened in normal controls, but it was not found in them. In silico modeling of PS2with Val and Leu at the position 214 was performed to contribute their molecular structures. The theoretical model (Figure below) revealed that this mutation might result significant structural modifications inside the PS2 protein, leading to overproduction of amyloid beta. Novel PSEN2 Val214Leu mutation at codon was found in two patients from unrelated families. One patient suffered from late-onset dementia without family history. The second patient is a 55-year-old woman whose only daughter has osteogenesis imperfecta. Since PS2 is component of the gamma-secretase complex, it could cleave the osteoblast regulator molecules. The mutation was absent in 128 control patients, supporting PSEN2 Val214Leu as a novel mutation for AD. Since Leu is more hydrophobic than Val, it might be possible, that Val->Leu exchange could result extra disturbances in the interactions between the TMIV helix and the membrane layer. Conclusions:We predicted the structures of presenilin 2 with native Val 214 residue and Leu 214 mutation, and the results revealed significant structural changes in the region. We found a probable novel mutation in the PSEN2 gene in two patients with Alzheimer’s disease from unrelated two families.