Estimation of the Genetic Contribution of Presenilin-1 and -2 Mutations in a Population-Based Study of Presenile Alzheimer Disease

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Human Molecular Genetics (Impact Factor: 6.39). 02/1998; 7(1):43-51. DOI: 10.1093/hmg/7.1.43
Source: PubMed


Two closely related genes, the presenilins ( PS ), located at chromosomes 14q24.3 and 1q42.1, have been identified for autosomal dominant Alzheimer disease (AD) with onset age below 65 years (presenile AD). We performed a systematic mutation analysis of all coding and 5'-non-coding exons of PS -1 and PS -2 in a population-based epidemiological series of 101 unrelated familial and sporadic presenile AD cases. The familial cases included 10 patients of autosomal dominant AD families sampled for linkage analysis studies. In all patients mutations in the amyloid precursor protein gene ( APP ) had previously been excluded. Four different PS -1 missense mutations were identified in six familial cases, two of which where autosomal dominant cases. Three mutations resulted in onset ages above 55 years, with one segregating in an autosomal dominant family with mean onset age 64 years (range 50-78 years). One PS -2 mutation was identified in a sporadic case with onset age 62 years. Our mutation data provided estimates for PS -1 and PS -2 mutation frequencies in presenile AD of 6 and 1% respectively. When family history was accounted for mutation frequencies for PS -1 were 9% in familial cases and 18% in autosomal dominant cases. Further, polymorphisms were detected in the promoter and the 5'-non-coding region of PS -1 and in intronic and exonic sequences of PS -2 that will be useful in genetic association studies.

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    • "N . S . Ryan et al . / Neurobiology of Aging xxx ( 2015 ) 1e12 8 median for the group ( 0 ) . This subject also carried the p . Arg62His PSEN2 variant . It was previously unclear whether this variant rep - resents a novel mutation or nonpathogenic polymorphism ( Cruts et al . , 1998 ) . Although it seems increasingly likely that it is not pathogenic ( Guerreiro et al . , 2010 ) , the possibility remains that it may have an influence on the clinicopathological phenotype ."
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    ABSTRACT: Familial Alzheimer's disease (FAD) treatment trials raise interest in the variable occurrence of cerebral amyloid angiopathy (CAA); an emerging important factor in amyloid-modifying therapy. Previous pathological studies reported particularly severe CAA with postcodon 200 PSEN1 mutations and amyloid beta coding domain APP mutations. As CAA may manifest as white matter hyperintensities (WMH) on magnetic resonance imaging, particularly posteriorly, we investigated WMH in 52 symptomatic FAD patients for associations with mutation position. WMH were visually rated in 39 PSEN1 (18 precodon 200); 13 APP mutation carriers and 25 healthy controls. Ten PSEN1 mutation carriers (5 precodon 200) had postmortem examination. Increased WMH were observed in the PSEN1 postcodon 200 group and in the single APP patient with an amyloid beta coding domain (p.Ala692Gly, Flemish) mutation. WMH burden on MRI correlated with severity of CAA and cotton wool plaques in several areas. The precodon 200 group had younger ages at onset, decreased axonal density and/or integrity, and a greater T-lymphocytic response in occipital deep white matter. Mutation site contributes to the phenotypic and pathological heterogeneity witnessed in FAD.
    Full-text · Article · Sep 2015 · Neurobiology of aging
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    • "with a probable deleterious effect . It clusters on the alpha helix surface of the fifth transmembrane domain ( TM5 ) , corresponds to a conserved residue among different species and in PSEN1 ( p . A231 ) , where 2 causative mutations ( p . A231V and p . A231T ) have been described in a Dutch , French and Canadian family ( Campion et al . , 1999 ; Cruts et al . , 1998 ; Rogaeva et al . , 2001 ) . The patient carrying the p . A237V variant was diagnosed at 87 years , homozygous for APOE ε3 allele , and did not refer any family history of AD ."
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    ABSTRACT: The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease, and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raises the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias.
    Full-text · Article · Jun 2014 · Neurobiology of Aging
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    • "Well-known mutations associated with autosomal dominant Alzheimer’s disease (AD) inheritance are amyloid precursor protein (APP) and presenilin 1 (PSEN1) and presenilin 2 (PSEN2) [1,2]. Previous studies have shown several APP and PSEN1 mutations in Asian populations, but pathogenic PSEN2 mutation has not yet been described [3,4]. "
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    ABSTRACT: Background PSEN2 mutations are rare variants, and fewer than 30 different PSEN2 mutations have been found. So far, it has not been reported in Asia. Case presentation PSEN2 mutation at codon 214 for predicting a valine to leucine substitution was found in a 70-year-old woman, who showed a dementia of the Alzheimer type. We did not find the mutation in 614 control chromosomes. We also predicted the structures of presenilin 2 protein with native Val 214 residue and Leu 214 mutation, which revealed significant structural changes in the region. Conclusion It could be a novel mutation verified with structural prediction in a patient with Alzheimer’s disease.
    Full-text · Article · May 2014 · BMC Neurology
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