Functional and genetic analysis of haplotypic sequence variation at the nicastrin genomic locus. Hamilton, G., Killick, R., Genetic, for Alzheimer's Disease Consortium, E. R., Translational Genomics Research Institute Consortium, Lambert, J., Amouyel, P., European Alzheimer Disease Initiative, Carrasquillo, M. M., Pankratz, V. S., Graff-Radford, N. R., Dickson, D. W., Petersen, R. C., Younkin, S. G., Powell, J. F., & Wade-Martins, R. Neurobiology of Aging, 33(8):1848.e1–13, August, 2012. doi abstract bibtex Nicastrin (NCSTN) is a component of the γ-secretase complex and therefore potentially a candidate risk gene for Alzheimer's disease. Here, we have developed a novel functional genomics methodology to express common locus haplotypes to assess functional differences. DNA recombination was used to engineer 5 bacterial artificial chromosomes (BACs) to each express a different haplotype of the NCSTN locus. Each NCSTN-BAC was delivered to knockout nicastrin (Ncstn(-/-)) cells and clonal NCSTN-BAC(+)/Ncstn(-/-) cell lines were created for functional analyses. We showed that all NCSTN-BAC haplotypes expressed nicastrin protein and rescued γ-secretase activity and amyloid beta (Aβ) production in NCSTN-BAC(+)/Ncstn(-/-) lines. We then showed that genetic variation at the NCSTN locus affected alternative splicing in human postmortem brain tissue. However, there was no robust functional difference between clonal cell lines rescued by each of the 5 different haplotypes. Finally, there was no statistically significant association of NCSTN with disease risk in the 4 cohorts. We therefore conclude that it is unlikely that common variation at the NCSTN locus is a risk factor for Alzheimer's disease.
@article{hamilton_functional_2012,
title = {Functional and genetic analysis of haplotypic sequence variation at the nicastrin genomic locus},
volume = {33},
issn = {1558-1497},
doi = {10.1016/j.neurobiolaging.2012.02.005},
abstract = {Nicastrin (NCSTN) is a component of the γ-secretase complex and therefore potentially a candidate risk gene for Alzheimer's disease. Here, we have developed a novel functional genomics methodology to express common locus haplotypes to assess functional differences. DNA recombination was used to engineer 5 bacterial artificial chromosomes (BACs) to each express a different haplotype of the NCSTN locus. Each NCSTN-BAC was delivered to knockout nicastrin (Ncstn(-/-)) cells and clonal NCSTN-BAC(+)/Ncstn(-/-) cell lines were created for functional analyses. We showed that all NCSTN-BAC haplotypes expressed nicastrin protein and rescued γ-secretase activity and amyloid beta (Aβ) production in NCSTN-BAC(+)/Ncstn(-/-) lines. We then showed that genetic variation at the NCSTN locus affected alternative splicing in human postmortem brain tissue. However, there was no robust functional difference between clonal cell lines rescued by each of the 5 different haplotypes. Finally, there was no statistically significant association of NCSTN with disease risk in the 4 cohorts. We therefore conclude that it is unlikely that common variation at the NCSTN locus is a risk factor for Alzheimer's disease.},
language = {eng},
number = {8},
journal = {Neurobiology of Aging},
author = {Hamilton, Gillian and Killick, Richard and {Genetic and Environmental Risk for Alzheimer's Disease Consortium} and {Translational Genomics Research Institute Consortium} and Lambert, Jean-Charles and Amouyel, Philippe and {European Alzheimer Disease Initiative} and Carrasquillo, Minerva M. and Pankratz, V. Shane and Graff-Radford, Neill R. and Dickson, Dennis W. and Petersen, Ronald C. and Younkin, Steven G. and Powell, John F. and Wade-Martins, Richard},
month = aug,
year = {2012},
pmid = {22405046},
pmcid = {PMC3683320},
keywords = {Alzheimer Disease, Humans, Molecular Sequence Data, Genetic Loci, Haplotypes, Membrane Glycoproteins, Amyloid Precursor Protein Secretases, Base Sequence, Chromosome Mapping},
pages = {1848.e1--13}
}
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F.","Wade-Martins, R."],"bibdata":{"bibtype":"article","type":"article","title":"Functional and genetic analysis of haplotypic sequence variation at the nicastrin genomic locus","volume":"33","issn":"1558-1497","doi":"10.1016/j.neurobiolaging.2012.02.005","abstract":"Nicastrin (NCSTN) is a component of the γ-secretase complex and therefore potentially a candidate risk gene for Alzheimer's disease. Here, we have developed a novel functional genomics methodology to express common locus haplotypes to assess functional differences. DNA recombination was used to engineer 5 bacterial artificial chromosomes (BACs) to each express a different haplotype of the NCSTN locus. Each NCSTN-BAC was delivered to knockout nicastrin (Ncstn(-/-)) cells and clonal NCSTN-BAC(+)/Ncstn(-/-) cell lines were created for functional analyses. We showed that all NCSTN-BAC haplotypes expressed nicastrin protein and rescued γ-secretase activity and amyloid beta (Aβ) production in NCSTN-BAC(+)/Ncstn(-/-) lines. We then showed that genetic variation at the NCSTN locus affected alternative splicing in human postmortem brain tissue. However, there was no robust functional difference between clonal cell lines rescued by each of the 5 different haplotypes. Finally, there was no statistically significant association of NCSTN with disease risk in the 4 cohorts. 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We therefore conclude that it is unlikely that common variation at the NCSTN locus is a risk factor for Alzheimer's disease.},\n\tlanguage = {eng},\n\tnumber = {8},\n\tjournal = {Neurobiology of Aging},\n\tauthor = {Hamilton, Gillian and Killick, Richard and {Genetic and Environmental Risk for Alzheimer's Disease Consortium} and {Translational Genomics Research Institute Consortium} and Lambert, Jean-Charles and Amouyel, Philippe and {European Alzheimer Disease Initiative} and Carrasquillo, Minerva M. and Pankratz, V. 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