Identification of New Presenilin Gene Mutations in Early-Onset Familial Alzheimer Disease

University of Florence, Florens, Tuscany, Italy
JAMA Neurology (Impact Factor: 7.42). 12/2003; 60(11):1541-4. DOI: 10.1001/archneur.60.11.1541
Source: PubMed


Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes, and more rarely in beta-amyloid precursor protein (betaAPP), underlie the pathogenesis of most cases of familial Alzheimer disease (FAD).
To screen the entire coding region of the PS1 and PS2 genes and exons 16 and 17 of the betaAPP to find pathogenetic mutations in FAD. Patients Patients with FAD were consecutively enrolled from among the outpatients from the neurology departments at the Universities of Florence and Parma and the Santa Maria Nuova Hospital in Reggio Emilia, Italy.
Polymerase chain reaction-single-strand conformation polymorphism and DNA se-quencing were used to investigate the affected members of families with FAD.
We identified a family carrying a novel Ser130Leu mutation in the PS2 gene. Moreover, we found 2 novel PS1 mutations: Cys92Ser in exon 4 in 2 unrelated families and Leu174Met in exon 6 in the PS1 gene. We also found a fourth Italian family with the betaAPP Val717Ile mutation.
One novel PS2 mutation associated with highly penetrant but variable age at onset (35-85 years) and 2 novel PS1 missense mutations associated with early-onset Alzheimer disease at age 49 to 54 years have been identified in Italian families. Screening for new mutations in presenilin and betaAPP genes was beneficial in characterizing gene function in FAD.

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    • "The third mosaic mutation, PSEN2 S130L, has been found before in an AD family [41] and was also found in an SAD case [42]. The pathogenicity of the PSEN2 S130L is disputed, as it has been also found in two healthy individuals, however, we note that in one instance the healthy subject was younger than the age of onset for this particular mutation [41], and in the second instance age was not disclosed [42]. In our cohort, we found the PSEN2 S130L variant as a nonmosaic heterozygous mutation also in a SAD patient, who displayed an age of onset at 66 years and died at 88 years of age. "
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    ABSTRACT: The cause of sporadic Alzheimer's disease (AD) remains unclear. Given the growing evidence that protein aggregates can spread in a "prion-like" fashion, we reasoned that a small population of brain cells producing such "prion-like" particles due to a postzygotic acquired mutation would be sufficient to trigger the disease. Deep DNA sequencing technology should in principle allow the detection of such mosaics. To detect the somatic mutations of genes causing AD present in a small number of cells, we developed a targeted deep sequencing approach to scrutinize the genomic loci of APP, PSEN1, and PSEN2 genes in DNA extracted from the entorhinal cortex, one of the brain regions showing the earliest signs of AD pathology. We also included the analysis of the MAPT gene because mutations may promote tangle formation. We validated candidate mutations with an independent targeted ultradeep amplicon sequencing technique. We demonstrate that our approach can detect single-nucleotide mosaic variants with a 1% allele frequency and copy number mosaic variants present in as few as 10% of cells. We screened 72 AD and 58 control brain samples and identified three mosaic variants with low allelic frequency (∼1%): two novel MAPT variants in sporadic AD patients and a known PSEN2 variant in a Braak II control subject. Moreover, we detected both novel and known pathogenic nonmosaic heterozygous variants in PSEN1 and PSEN2 in this cohort of sporadic AD patients. Our results show that mosaic mutations with low allelic frequencies in AD-relevant genes can be detected in brain-derived DNA, but larger samples need to be investigated before a more definitive conclusion with regard to the pathogenicity of such mosaics can be made. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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    • "PSEN2 mutations alter the cleavage activity of the -secretase complex and increase the ratio of AA 42 to A 40 . Mutations are estimated to have 95% penetrance , in contrast with APP and PSEN1 mutations which are thought to be fully penetrant, and are associated with later age of onset and slower disease progression than the other autosomal dominant mutations [46] [47] [48] [49]. Mutations within APP, PSEN1 and PSEN2, account for up to 71% of the familial autosomal dominant cases of AD [50]. "
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    ABSTRACT: Early Onset Alzheimer Disease (EOAD) is a rare condition, frequently associated with genetic causes. The dissemination of genetic testing along with biomarker determinations have prompted a wider recognition of EOAD in experienced clinical settings. However, despite the great efforts in establishing the contribution of causative genes to EOAD, atypical disease presentation and clinical features still makes its diagnosis and treatment a challenge for the clinicians. This review aims to provide an extensive evaluation of literature data on EOAD, in order to improve understanding and knowledge of EOAD, underscore its significant impact on patients and their caregivers and influence public policies. This would be crucial to define the urgency of evidence-based treatment approaches.
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    • "Of these, 1 was a probable pathogenic mutation of PSEN1 (p.T122A), determined using Polyphen-2 (Adzhubei et al., 2010) analysis (probably damaging score ¼ 0.999) and the variant position in the protein adjacent to well characterized mutations, and the others were possible pathogenic mutations (including a missense variant of MAPT p.R472G, which is predicted to be damaging by Polyphen-2 (score=0.999)). Of particular note were 2 cases from the 10 included in our validation panel with dementia associated with genetic variants of uncertain significance (VCP p.I27V) (Rohrer et al., 2011) and PSEN2 (p.S130L) (Tedde et al., 2003). VCP p.I27V was found together with PSEN1 p.T122A; and PSEN2 (p.S130L) was found together with GRN p.R473X. "
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