Presenilin-1 mutation E318G and familial Alzheimer's disease in the Italian population

Albani, Diego; Roiter, Ignazio; Artuso, Vladimiro; Batelli, Sara; Prato, Francesca; Pesaresi, Marzia; Galimberti, Daniela; Scarpini, Elio; Bruni, Amalia C.; Franceschi, M.; Piras, Maria Rita; Confaloni, Annamaria; Forloni, Gianluigi

doi:10.1016/j.neurobiolaging.2006.07.003

Cited by 21 publications

(21 citation statements)

References 31 publications

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“…PSEN1 -92delC was found in AD patients with an allele frequency 0.005 (8/1632 chromosomes). PSEN1 E318G was previously detected in AD patients with an allele frequency 0.02 (12/596 chromosomes)21,25 which is the same as the frequency we obtained by testing late-onset AD patients from NIMH samples. PSEN2 R62H missense mutation was detected in AD patients with an allele frequency 0.016 (5/320 chromosomes).…”

Section: Resultssupporting

confidence: 84%

Protein Aggregates and Novel Presenilin Gene Variants in Idiopathic Dilated Cardiomyopathy

et al. 2010

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Background-Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of ␤-amyloid impair cell function and lead to cell death. Methods and Results-We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca 2ϩ homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. Conclusions-On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca 2ϩ handling and a direct effect of PSEN1 sequence variants on excitationcontraction coupling protein function. (Circulation. 2010;121:1216-1226.) Key Words: calcium Ⅲ cardiomyopathy Ⅲ genetics Ⅲ heart failure Ⅲ myocytes I n 1906, Alois Alzheimer discovered, in the brain of a patient suffering from early-age onset of dementia, aggregates of a proteinaceous material, later identified to be composed of amyloid fibers. 1 Alzheimer disease (AD) is associated with several genetic defects and the abnormal accumulation of the amyloid-␤ protein (A␤) and in the form of extracellular (senile plaques) and intracellular (neurofibrillar tangles) aggregates, respectively. 2 In the heart, amyloid degeneration leading to dilated cardiomyopathy (DCM) has been limited to 3 conditions: (1) light-chain amyloidosis secondary to multiple myeloma; (2) transthyretin cardiomyopathy 3 ; and (3) desmin cardiomyopathy. 4,5 In a smaller number of cases of nonischemic origin, the pathogenesis of heart failure (HF) is infective, toxic, or genetically determined. When 1 of these causative events cannot be recognized, the myocardial disease is classified as idiopathic DCM (iDCM). Clinical Perspective on p 1226Genetically, DCM has been found in only 35% of HF cases, indicating that the cause of this disease remains largely unknown. 6 Mutations in genes encoding sarcomeric, cytoskeletal, and nuclear proteins as well as proteins involved in the regulation of Ca 2ϩ homeostasis have been described. 7,8 Allelic and locus heterogeneities occur in DCM, 9 and these alterations, together with environmental factors, can disclose an otherwise silent genetic background as occurs in neurodegenerative diseases. Recently, 2 mutations in the familial early-onset AD-associated presenilin genes (PSEN1 D333G and PSEN2 S130L), 2 have been found in 0.9% of tested DCM families (3/325). 10 The presenilins (PS1 and PS2) are highly conserved polytopic membrane proteins that are required for ␥-secretase activity, an enzyme responsible for proteolytic processing of the amyloid precursor protein to genera...

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Section: Resultssupporting

confidence: 84%

Protein Aggregates and Novel Presenilin Gene Variants in Idiopathic Dilated Cardiomyopathy

et al. 2010

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“…In previous Finnish, Australian, and Italian studies, a connection has been observed between late-onset AD and E318G, suggesting that the increased risk may be age dependent and that the variation may contribute more to late-onset AD. 26,42,43 In our series, the frequency of ApoEE4 allele carriers was very high in the entire eoAD group (61.4%) and even higher in the familial eoAD cases (70.1%), being 2 times higher than the frequency in controls (33.7%). The ApoEE4 allele of the ApoE gene is by far the most firmly established genetic risk factor for both familial and sporadic late-onset AD and also for eoAD.…”

Section: Discussionmentioning

confidence: 40%

“…26 In addition, significant associations between the E318G mutation and familial late-onset AD have been reported in Australian and Italian populations. 42,43 In our cohort, the E318G variant was detected with similar frequencies among the cases of eoAD and FTLD and among the healthy controls, suggesting no association with eoAD. In previous Finnish, Australian, and Italian studies, a connection has been observed between late-onset AD and E318G, suggesting that the increased risk may be age dependent and that the variation may contribute more to late-onset AD.…”

Section: Discussionmentioning

confidence: 54%

Molecular Genetic Analysis of the APP, PSEN1, and PSEN2 Genes in Finnish Patients With Early-onset Alzheimer Disease and Frontotemporal Lobar Degeneration

Krüger

Moilanen²,

Majamaa³

et al. 2012

Alzheimer Disease &Amp; Associated Disorders

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Mutations in 3 genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been identified as causing a proportion of early-onset Alzheimer disease (eoAD) cases. A few PSEN mutations have also been previously detected in patients with frontotemporal lobar degeneration (FTLD). In order to evaluate the role of these genes in a clinical series of Finnish eoAD and FTLD patients, we sequenced exons 16 and 17 of the APP gene and the coding regions of the PSEN1 and PSEN2 genes in 140 eoAD and 66 FTLD patients. No pathogenic mutations were identified in the cohort. The E318G variant was detected with similar frequencies in the cases with eoAD and FTLD and the healthy controls, therefore, showing no association between E318G and eoAD. Furthermore, the PSEN2 R71W variant seems to be nonpathogenic, because it was present in our healthy controls. Mutations in the PSEN1, PSEN2, and APP genes seem to be rare in this population, as these genes exhibited no pathogenic mutations in our cohort of eoAD and FTLD patients even though about 40% of the cases were familial ones. This suggests the involvement of other, still unknown genetic factors in the pathogenesis of these diseases.

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“…The pathogenic role of PS1 Glu318Gly polymorphism has been so far debated in the literature [9][10][11]. From our study it is impossible to obtain a conclusive response about its pathogenicity: we cannot exclude involvement of the polymorphism in causing the disease, in association (or not) with APOE genotype and PS2 mutation.…”

mentioning

confidence: 81%

Late onset familial Alzheimer's disease: novel presenilin 2 mutation and PS1 E318G polymorphism

et al. 2008

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Presenilin-1 mutation E318G and familial Alzheimer's disease in the Italian population

Cited by 21 publications

References 31 publications

Protein Aggregates and Novel Presenilin Gene Variants in Idiopathic Dilated Cardiomyopathy

Protein Aggregates and Novel Presenilin Gene Variants in Idiopathic Dilated Cardiomyopathy

Molecular Genetic Analysis of the APP, PSEN1, and PSEN2 Genes in Finnish Patients With Early-onset Alzheimer Disease and Frontotemporal Lobar Degeneration

Late onset familial Alzheimer's disease: novel presenilin 2 mutation and PS1 E318G polymorphism

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