BACKGROUND: Deposits of abnormally hyperphosphorylated tau are a hallmark of several dementias, including Alzheimer disease (AD), and about 10% of familial frontotemporal dementia (FTD) cases are caused by mutations in the tau gene. As a known tau kinase, GSK3B is a promising candidate gene in the remaining cases of FTD and in AD, for which tau mutations have not been found. OBJECTIVE: To examine the promoter of GSK3B and all 12 exons, including the surrounding intronic sequence, in patients with FTD, patients with AD, and aged healthy subjects to identify single-nucleotide polymorphisms associated with disease. DESIGN, SETTING, AND PARTICIPANTS: Single-nucleotide polymorphism frequency was examined in a case-control cohort of 48 patients with probable AD, 102 patients with FTD, 38 patients with primary progressive aphasia, and 85 aged healthy subjects. Results were followed up in 2 independent AD family samples consisting of 437 multiplex families with AD (National Institute of Mental Health Genetics Initiative AD Study) or 150 sibships discordant for AD (Consortium on Alzheimer's Genetics Study). RESULTS: Several rare sequence variants in GSK3B were identified in the case-control study. An intronic polymorphism (IVS2-68G>A) occurred at more than twice the frequency among patients with FTD (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%). The polymorphism showed association with disease in both follow-up samples independently, although only the Consortium on Alzheimer's Genetics sample showed the same direction of association as the case-control sample. CONCLUSIONS: To our knowledge, this is the first evidence that a gene known to be involved in tau phosphorylation, GSK3B, is associated with risk for primary neurodegenerative dementias. This supports previous work in animal models suggesting that such genes are therapeutic targets.
BACKGROUND: Deposits of abnormally hyperphosphorylated tau are a hallmark of several dementias, including Alzheimer disease (AD), and about 10% of familial frontotemporal dementia (FTD) cases are caused by mutations in the tau gene. As a known tau kinase, GSK3B is a promising candidate gene in the remaining cases of FTD and in AD, for which tau mutations have not been found. OBJECTIVE:To examine the promoter of GSK3B and all 12 exons, including the surrounding intronic sequence, in patients with FTD, patients with AD, and aged healthy subjects to identify single-nucleotide polymorphisms associated with disease. DESIGN, SETTING, AND PARTICIPANTS: Single-nucleotide polymorphism frequency was examined in a case-control cohort of 48 patients with probable AD, 102 patients with FTD, 38 patients with primary progressive aphasia, and 85 aged healthy subjects. Results were followed up in 2 independent AD family samples consisting of 437 multiplex families with AD (National Institute of Mental Health Genetics Initiative AD Study) or 150 sibships discordant for AD (Consortium on Alzheimer's Genetics Study). RESULTS: Several rare sequence variants in GSK3B were identified in the case-control study. An intronic polymorphism (IVS2-68G>A) occurred at more than twice the frequency among patients with FTD (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%). The polymorphism showed association with disease in both follow-up samples independently, although only the Consortium on Alzheimer's Genetics sample showed the same direction of association as the case-control sample. CONCLUSIONS:To our knowledge, this is the first evidence that a gene known to be involved in tau phosphorylation, GSK3B, is associated with risk for primary neurodegenerative dementias. This supports previous work in animal models suggesting that such genes are therapeutic targets.
Authors: Deborah Blacker; Lars Bertram; Aleister J Saunders; Thomas J Moscarillo; Marilyn S Albert; Howard Wiener; Rodney T Perry; Julianne S Collins; Lindy E Harrell; Rodney C P Go; Amy Mahoney; Terri Beaty; M Danielle Fallin; Dimitrios Avramopoulos; Gary A Chase; Marshal F Folstein; Melvin G McInnis; Susan S Bassett; Kimberly J Doheny; Elizabeth W Pugh; Rudolph E Tanzi Journal: Hum Mol Genet Date: 2003-01-01 Impact factor: 6.150
Authors: J P Brion; B H Anderton; M Authelet; R Dayanandan; K Leroy; S Lovestone; J N Octave; L Pradier; N Touchet; G Tremp Journal: Biochem Soc Symp Date: 2001
Authors: D H Geschwind; J Robidoux; M Alarcón; B L Miller; K C Wilhelmsen; J L Cummings; Z S Nasreddine Journal: Ann Neurol Date: 2001-12 Impact factor: 10.422
Authors: George R Jackson; Martina Wiedau-Pazos; Tzu-Kang Sang; Naveed Wagle; Carlos A Brown; Sasan Massachi; Daniel H Geschwind Journal: Neuron Date: 2002-05-16 Impact factor: 17.173
Authors: Preeti J Khandelwal; Sonya B Dumanis; Alexander M Herman; G William Rebeck; Charbel E-H Moussa Journal: Mol Cell Neurosci Date: 2011-09-14 Impact factor: 4.314
Authors: Jing Li; Fan Zeng; Juan Deng; Jie Zhu; Lin Li; Tao Zhang; Juan Liu; Li-Li Zhang; Chang-Yue Gao; Meng Zhang; Zhi-Qiang Xu; Hua-Dong Zhou; Yan-Jiang Wang Journal: Neurotox Res Date: 2014-08-21 Impact factor: 3.911
Authors: Juan Manuel Domínguez; Ana Fuertes; Leyre Orozco; María del Monte-Millán; Elena Delgado; Miguel Medina Journal: J Biol Chem Date: 2011-11-18 Impact factor: 5.157
Authors: Shashwath A Meda; Mary Ellen I Koran; Jennifer R Pryweller; Jennifer N Vega; Tricia A Thornton-Wells Journal: Neurobiol Aging Date: 2012-10-27 Impact factor: 4.673