title: Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques.
abstract: We describe the biological consequences on PSEN1 exons 8 or 9 splicing and Abeta peptides production of four PSEN1 mutations associated with a phenotypic variant of Alzheimer disease, which includes cotton wool plaques and spastic paraparesis (CWP/SP). Two of these mutations (c.869-22_869-23ins18 and c.871A > C, p.T291P) are novel mutations located in intron 8 and exon 9, respectively. The c.869-22_869-23ins18 mutation caused exon 9 skipping whereas the c.871A > C (p.T291P) mutation showed only a modest effect on exon 9 skipping. The previously reported E280G and P264L mutations, located in exon 8, had no effect on mRNA splicing. Infection of cells with mutant T291P, E280G, or P264L cDNAs caused a variable increase in secreted Abeta42. We conclude that none of the previously proposed mechanisms, i.e. exceptionally large increases in secreted Abeta42 levels or loss of PSEN1 exons 8 or 9, provides complete explanation of the CWP/SP phenotype.
authors.affiliation: Inserm U614, IFRMP, Faculté de Médecine, Rouen, France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Dumanchin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tournier
authors.forename: Cosette
authors.initials: C
authors.lastname: Martin
authors.forename: Mira
authors.initials: M
authors.lastname: Didic
authors.forename: Serge
authors.initials: S
authors.lastname: Belliard
authors.forename: Bertrand
authors.initials: B
authors.lastname: Carlander
authors.forename: François
authors.initials: F
authors.lastname: Rouhart
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Pellissier
authors.forename: Jean Baptiste
authors.initials: JB
authors.lastname: Latouche
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.forename: Mario
authors.initials: M
authors.lastname: Tosi
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D004252:DNA Mutational Analysis; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020336:Paraparesis, Spastic / Q000473:pathology*; D058225:Plaque, Amyloid / Q000473:pathology*; D053764:Presenilin-1; D012326:RNA Splicing / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1