Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques.
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.
Dumanchin
Cecile
C
Inserm U614, IFRMP, Faculté de Médecine, Rouen, France.
Tournier
Isabelle
I
Martin
Cosette
C
Didic
Mira
M
Belliard
Serge
S
Carlander
Bertrand
B
Rouhart
François
F
Duyckaerts
Charles
C
Pellissier
Jean-François
JF
Latouche
Jean Baptiste
JB
Hannequin
Didier
D
Frebourg
Thierry
T
Tosi
Mario
M
Campion
Dominique
D
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
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1