Abstract:
:Presenilin 1 (PSEN1) mutations are the main cause of autosomal dominant Early-onset Alzheimer Disease (EOAD). Among them, deletions of exon 9 have been reported to be associated with a phenotype of spastic paraparesis. Using exome data from a large sample of 522 EOAD cases and 584 controls to search for genomic copy-number variations (CNVs), we report here a novel partial, in-frame deletion of PSEN1, removing both exons 9 and 10. The patient presented with memory impairment associated with spastic paraparesis, both starting from the age of 56years. He presented a positive family history of EOAD. We performed functional analysis to elucidate the impact of this novel deletion on PSEN1 activity as part of the γ-secretase complex. The deletion does not affect the assembly of a mature protease complex but has an extreme impact on its global endopeptidase activity. The mutant carboxypeptidase-like activity is also strongly impaired and the deleterious mutant effect leads to an incomplete digestion of long Aβ peptides and enhances the production of Aβ43, which has been shown to be potently amyloidogenic and neurotoxic in vivo.
journal_name
Neurobiol Disjournal_title
Neurobiology of diseaseauthors
Le Guennec K,Veugelen S,Quenez O,Szaruga M,Rousseau S,Nicolas G,Wallon D,Fluchere F,Frébourg T,De Strooper B,Campion D,Chávez-Gutiérrez L,Rovelet-Lecrux Adoi
10.1016/j.nbd.2017.04.020subject
Has Abstractpub_date
2017-08-01 00:00:00pages
97-103eissn
0969-9961issn
1095-953Xpii
S0969-9961(17)30102-Xjournal_volume
104pub_type
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