Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Export

@article{citeulike:2924165, abstract = {OBJECTIVE: Loss-of-function mutations in the progranulin gene (PGRN) were identified in frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusions (FTLD-U). We assessed whether PGRN also contributes to genetic risk for Alzheimer disease (AD) in an extended Belgian AD patient group (n = 779, onset age 74.7 +/- 8.7 years). METHODS: A mutation analysis of the PGRN coding region was performed. The effect of missense mutations was assessed using in silico predictions and protein modeling. Risk effects of common genetic variants were estimated by logistic regression analysis and gene-based haplotype association analysis. RESULTS: We observed seven missense mutations in eight patients (1.3\%). Convincing pathogenic evidence was obtained for two missense mutations, p.Cys139Arg and p.Pro451Leu, affecting PGRN protein folding and leading to loss of PGRN by degradation of the misfolded protein. In addition, we showed that PGRN haplotypes were associated with increased risk for AD. CONCLUSIONS: Our data support a role for PGRN in patients with clinically diagnosed Alzheimer disease (AD). Further, we hypothesize that at least some PGRN missense mutations might lead to loss of functional protein. Whether the underlying pathology in our cases proves to be AD, frontotemporal lobar degeneration, or a combination of the two must await further investigations.}, address = {From Neurodegenerative Brain Diseases Group (N.B., K.S., I.G., J.v.d.Z., M.V.d.B., M.M., K.P., M.C., C.V.B.), Department of Molecular Genetics and SWITCH Laboratory (S.M.-S., J.S., F.R.), VIB; Laboratory of Neurogenetics (N.B., K.S., I.G., J.v.d.Z., M.V.d.B., M.M., K.P., M.C., C.V.B.), Laboratory of Neurochemistry and Behaviour (S.E., P.P.D.D.), and Laboratory of Neuropathology (J.-J.M.), Institute Born-Bunge; University of Antwerp (N.B., K.S., S.E., I.G., J.v.d.Z., M.V.d.B., M.M., K.P., J.-J.M., M.C., P.P.D.D., C.V.B.), Antwerpen; University of Brussels (VUB) (S.M.-S., J.S., F.R.); and Memory Clinic and Department of Neurology (S.E., B.A.P., P.P.D.D.), Middelheim General Hospital, Antwerpen, Belgium.}, author = {Brouwers, N and Sleegers, K and Engelborghs, S and Maurer-Stroh, S and Gijselinck, I and van der Zee, J and Pickut, B A A. and Van den Broeck, M and Mattheijssens, M and Peeters, K and Schymkowitz, J and Rousseau, F and Martin, J-J J. and Cruts, M and De Deyn, P P P. and Van Broeckhoven, C}, citeulike-article-id = {2924165}, citeulike-linkout-0 = {http://dx.doi.org/10.1212/01.wnl.0000319688.89790.7a}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18565828}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18565828}, day = {18}, doi = {10.1212/01.wnl.0000319688.89790.7a}, issn = {1526-632X}, journal = {Neurology}, keywords = {ad, genetics, prgn, risk}, month = {June}, posted-at = {2008-10-03 14:39:28}, priority = {1}, title = {Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease.}, url = {http://dx.doi.org/10.1212/01.wnl.0000319688.89790.7a}, year = {2008} }

TY - JOUR ID - citeulike:2924165 L3 - citeulike-article-id:2924165 N2 - OBJECTIVE: Loss-of-function mutations in the progranulin gene (PGRN) were identified in frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusions (FTLD-U). We assessed whether PGRN also contributes to genetic risk for Alzheimer disease (AD) in an extended Belgian AD patient group (n = 779, onset age 74.7 +/- 8.7 years). METHODS: A mutation analysis of the PGRN coding region was performed. The effect of missense mutations was assessed using in silico predictions and protein modeling. Risk effects of common genetic variants were estimated by logistic regression analysis and gene-based haplotype association analysis. RESULTS: We observed seven missense mutations in eight patients (1.3%). Convincing pathogenic evidence was obtained for two missense mutations, p.Cys139Arg and p.Pro451Leu, affecting PGRN protein folding and leading to loss of PGRN by degradation of the misfolded protein. In addition, we showed that PGRN haplotypes were associated with increased risk for AD. CONCLUSIONS: Our data support a role for PGRN in patients with clinically diagnosed Alzheimer disease (AD). Further, we hypothesize that at least some PGRN missense mutations might lead to loss of functional protein. Whether the underlying pathology in our cases proves to be AD, frontotemporal lobar degeneration, or a combination of the two must await further investigations. JF - Neurology SN - 1526-632X AD - From Neurodegenerative Brain Diseases Group (N.B., K.S., I.G., J.v.d.Z., M.V.d.B., M.M., K.P., M.C., C.V.B.), Department of Molecular Genetics and SWITCH Laboratory (S.M.-S., J.S., F.R.), VIB; Laboratory of Neurogenetics (N.B., K.S., I.G., J.v.d.Z., M.V.d.B., M.M., K.P., M.C., C.V.B.), Laboratory of Neurochemistry and Behaviour (S.E., P.P.D.D.), and Laboratory of Neuropathology (J.-J.M.), Institute Born-Bunge; University of Antwerp (N.B., K.S., S.E., I.G., J.v.d.Z., M.V.d.B., M.M., K.P., J.-J.M., M.C., P.P.D.D., C.V.B.), Antwerpen; University of Brussels (VUB) (S.M.-S., J.S., F.R.); and Memory Clinic and Department of Neurology (S.E., B.A.P., P.P.D.D.), Middelheim General Hospital, Antwerpen, Belgium. TI - Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. KW - ad KW - genetics KW - prgn KW - risk AU - Brouwers, N AU - Sleegers, K AU - Engelborghs, S AU - Maurer-Stroh, S AU - Gijselinck, I AU - van der Zee, J AU - Pickut, B A AU - Van den Broeck, M AU - Mattheijssens, M AU - Peeters, K AU - Schymkowitz, J AU - Rousseau, F AU - Martin, J-J AU - Cruts, M AU - De Deyn, P P AU - Van Broeckhoven, C PY - 2008/06/18/ UR - http://dx.doi.org/10.1212/01.wnl.0000319688.89790.7a ER -