The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families

Clark, Robert; Hutton, Michael; Fuldner, Rebecca A.; Froelich, Susanne; Karran, Eric; Talbot, Chris J.; Crook, Richard; Lendon, Corinne; Prihar, Guy; He, Chuan; Korenblat, Kevin; Martínez, Alonso; Wragg, Michelle; Busfield, Frances; Behrens, María Isabel; Myers, Amanda; Norton, Joanne; Morris, John C.; Mehta, Nitin D.; Pearson, Christopher; Lincoln, Sarah; Baker, Matt; Duff, Karen; Zehr, Cindy; Pérez‐Tur, Jordi; Houlden, H; Ruíz, A Navarro; Ossa, Jorge; Lopera, Francisco; Arcos, Mauricio; Madrigal, Lucía; Collinge, John; Humphreys, Christopher M.; Ashworth, Todd; Sarner, S; Fox, Nick C.; Harvey, Richard J; Kennedy, Angus; Roques, P; Cline, Robert J.; Phillips, Carissa; Venter, J. Craig; Forsell, L; Axelman, Karin; Lilius, Lena; Johnston, Janet; Cowburn, Richard F.; Viitanen, Matti; Winblad, Bengt; Kosik, KS; Haltia, Matti; Pöyhönen, Minna; Dickson, Dennis W.; Mann, David; Neary, David; Snowden, Julie S.; Lantos, PL; Lannfelt, Lars; Rossor, Martin N.; Roberts, George T.; Adams, Mark D.; Hardy, John; Goate, Alison M.

doi:10.1038/ng1095-219

Cited by 417 publications

(117 citation statements)

References 19 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…However, our N-terminal antibody does not recognize the rat PS1 homolog and, therefore, does not detect PS1 in untransfected PC12 cells. Because both the 49 and 32 kDa species seen in our expression systems derive from a full-length human PS1 cDNA, we can exclude the possibility that the various polypeptides arise by alternative splicing (Clark et al, 1995;Rogaev et al, 1995;Anwar et al, 1996;Sahara et al, 1996). Recently, endoproteolytic cleavage of PS1 resulting in regulated accumulation of Nand C-terminal derivatives has been reported in transgenic mice .…”

Section: Discussionmentioning

confidence: 99%

“…The resulting fragments were subcloned independently into pCDNA3 (Invitrogen, San Diego, CA), and the sequences were verified by dideoxy sequencing (Sequenase, Amersham, Arlington Heights, IL). The PS1 clone contains all known exons (Clark et al, 1995) and codes for a full-length protein of 467 amino acids. Our full-length PS2 clone contains 50 base pairs of 5Ј untranslated and 30 base pairs of 3Ј untranslated sequence, and it is predicted to encode a protein of 448 amino acids.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Light and Electron Microscopic Localization of Presenilin-1 in Primate Brain

et al. 1997

View full text Add to dashboard Cite

Several genes have been implicated in the pathogenesis of early-onset familial Alzheimer's disease. A majority of the autosomal dominant cases are linked to recently identified mutations in the presenilin-1 gene on chromosome 14. The native presenilin-1 protein in primates has not been well characterized, and its precise localization is unknown. We have studied the native presenilin-1 protein in monkey brain and peripheral tissues by using a monoclonal antibody specific for the N-terminal domain of human presenilin-1. Western blots detect polypeptide species of ϳ49 and ϳ32 kDa from COS-7 and PC12 cells transfected with full-length human presenilin-1 cDNA and from in vitro translations of the normal human presenilin-1 mRNA. A 32 kDa polypeptide is detected in monkey peripheral tissues, with the highest expression in testis and lung. In all brain regions the 32 kDa band is the predominant form of presenilin-1, and it is found in particulate subfractions. Light microscopic immunocytochemistry reveals presenilin-1 staining in all brain regions, with the strongest labeling in neurons and neuropil. In addition, weaker immunoreactivity is also present in glia and blood vessels. Neuronal staining shows significant variability, with particularly intense labeling of certain cell types, including large neocortical and hippocampal pyramidal neurons, magnocellular basal forebrain neurons, brainstem motoneurons, and some populations of interneurons. By electron microscopic immunocytochemistry, highly selective presenilin-1 staining is seen on the cytoplasmic surfaces of membranous organelles, which suggest localization to the endoplasmic reticulum-Golgi intermediate compartment, a subdomain of the endoplasmic reticulum, and some coated transport vesicles.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Light and Electron Microscopic Localization of Presenilin-1 in Primate Brain

et al. 1997

View full text Add to dashboard Cite

show abstract

“…Full-length cDNAs encoding human wtPS1 and PS1 M146V were the generous gift of Dr. John Hardy (Clark et al, 1995). Synthesis of m 7 G(5Ј)ppp(5Ј)Gcapped cRNA was performed by run-off transcription of template plasmids linearized with the restriction endonuclease XbaI using the Riboprobe Gemini System (Promega) according to the manufacturer's recommendations.…”

Section: Crna Synthesis and Injectionmentioning

confidence: 99%

Subcellular Mechanisms of Presenilin-Mediated Enhancement of Calcium Signaling

Leissring

LaFerla

Callamaras

et al. 2001

Neurobiology of Disease

View full text Add to dashboard Cite

Mutations in presenilin-1 (PS1), the leading cause of early-onset, autosomal-dominant familial Alzheimer's disease (FAD), enhance calcium signaling mediated by inositol 1,4,5-trisphosphate (IP 3 ). To elucidate the subcellular mechanisms underlying this enhancement, we used high resolution linescanning confocal microscopy to image elementary calcium release events ("puffs") in Xenopus oocytes expressing wild-type or mutant PS1. Here we report that mutant PS1-rendered puffs more sensitive to IP 3 and increased both the magnitude and the rate of calcium release during each event. These effects were not attributable to quantitative changes in the levels of IP 3 receptors or their distribution on the ER, but were instead associated with an abnormal elevation of ER calcium stores. Together, our results suggest that the effects of mutant PS1 on calcium signaling are manifested predominantly at the level of the regulation of calcium stores rather than via perturbations in the numbers or activity of IP 3 -activated calcium release channels.

show abstract

“…1,5,13 Early progressive aphasia, myoclonus, generalized seizures, and paratonia are apparently more common in PS-1-encoded FAD than in patients with APP (codon 717) mutation. 14 In addition, there are a few reports on phenotypic heterogeneity between different mutations of the same gene.…”

mentioning

confidence: 99%

“…15 Headache was reported to be a distinctive symptom in FAD due to the E280A mutation of the PS-1 gene, 16 whereas early and prominent myoclonus mimicking Creutzfeldt-Jakob disease was found to be associated with the M146V mutation of the same gene. 5,17 We recently reported a variant form of FAD, due to deletion of exon 9 of PS-1, with unusual cortical "cotton wool" plaques at neuropathologic analysis.…”

mentioning

confidence: 99%

MICAL-1 Is a Negative Regulator of MST-NDR Kinase Signaling and Apoptosis

Zhou

Adolfs

Pijnappel

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

Article abstract-Objective: To present the clinical, neuroimaging, and electrophysiologic characteristics of a variant AD phenotype. Background: The authors have identified a large Finnish kindred with presenile dementia and spastic paraparesis due to deletion of exon 9 of presenilin 1. Neuropathologic analysis showed unusual cortical "cotton wool" plaques, immunoreactive for the beta-amyloid peptide but lacking congophilic cores. Patients and Methods: Twenty-two affected individuals (16 men and 6 women) were identified in four successive generations. All surviving five patients were examined and subjected to molecular genetic analysis. In addition, the neurologic records of nine deceased patients were evaluated. Electrophysiologic investigations were available in eight cases. CT or MRI of the head had been performed on 11 patients and PET was performed on three patients. Result: The mean age at onset (ϮSD) was 50.9 Ϯ 5.2 years (range 40 to 61 years). Memory impairment was present in all patients. Memory impairment appeared simultaneously with or was preceded by walking difficulty due to spasticity of the lower extremities (10/14). Impaired fine coordination of hands (9/14) and dysarthria (6/14) in some patients suggested cerebellar involvement. EEG showed intermittent generalized delta-theta activity. Head MRI showed temporal and hippocampal atrophy; PET showed bilateral temporo-parietal hypometabolism. Conclusion: Spastic paraparesis or brisk stretch reflexes of lower extremities or clumsiness of hands combined with dementia suggests this variant of AD.

show abstract

The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families

Cited by 417 publications

References 19 publications

Light and Electron Microscopic Localization of Presenilin-1 in Primate Brain

Light and Electron Microscopic Localization of Presenilin-1 in Primate Brain

Subcellular Mechanisms of Presenilin-Mediated Enhancement of Calcium Signaling

MICAL-1 Is a Negative Regulator of MST-NDR Kinase Signaling and Apoptosis

Contact Info

Product

Resources

About