APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy

Rovelet‐Lecrux, Anne; Hannequin, Didier; Raux, Grégory; Meur, Nathalie Le; Laquerrière, Annie; Vital, Anne; Dumanchin, Cécile; Feuillette, Sébastien; Brice, Alexis; Vercelletto, Martine; Dubas, Frédéric; Frébourg, Thierry; Campion, Dominique

doi:10.1038/ng1718

Cited by 1,061 publications

(773 citation statements)

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“…Finally, it is relevant that early onset FAD has been reported in six families carrying a duplication of one of their APP genes and that APP promoter mutations that increase expression are linked to increased AD risk [35,42,44]. Furthermore, women who have a Downs syndrome/ trisomy 21 child before the age of 35 are usually aneuploid for trisomy 21 themselves and have a five-fold increased risk of developing AD later in life [26,37,38].…”

Section: Discussionmentioning

confidence: 99%

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Boeras

Granic

Padmanabhan

et al. 2008

Neurobiology of Aging

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Mutations in the presenilin 1 gene cause most early-onset familial Alzheimer's disease (FAD). Here we report that a defect in the cell cycle-improper chromosome segregation-can be caused by abnormal presenilin function and therefore may contribute to AD pathogenesis. Specifically we find that either over-expression or FAD mutation in presenilin 1 (M146L and M146V) leads to chromosome missegregation and aneuploidy in vivo and in vitro: 1) Up to 20% of lymphocytes and neurons of FAD-PS-1 transgenic and knockin mice are aneuploid by metaphase chromosome analysis and in situ hybridization, 2) Transiently transfected human cells over-expressing normal or mutant PS-1 develop similar aneuploidy within 48 hours, including trisomy 21. 3) Mitotic spindles in the PS-1 transfected cells contain abnormal microtubule arrays and lagging chromosomes. Several mechanisms by which chromosome missegregation induced by presenilin may contribute to Alzheimer's disease are discussed.

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Section: Discussionmentioning

confidence: 99%

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Boeras

Granic

Padmanabhan

et al. 2008

Neurobiology of Aging

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“…Following our national guidelines for AD genetic diagnosis in EOAD, we sequenced the entire coding region of PSEN1, PSEN2 and exons 16 and 17 of APP by Sanger method and searched for APP duplication by QMPSF as previously described 8 in patients with ADEOAD and in patients with sporadic AD with an age of onset before 51 years.…”

Section: Patients and Methods Patientsmentioning

confidence: 99%

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Nicolas¹,

Wallon²,

Charbonnier³

et al. 2015

Eur J Hum Genet

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Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of lateonset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.

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“…15 In the Dutch population, duplication of the APP gene has been reported and was found to be associated with autosomal dominant early-onset AD and cerebral amyloid angiopathy. [14][15][16] It is interesting to note the association of the Alzheimer's with Down's syndrome that is due to trisomy 21. APP gene maps on the same chromosome so those with Down's syndrome have three copies of the gene and are more prone to Alzheimer's.…”

Section: Cnv and Neurological Disordersmentioning

confidence: 99%