Mutation analysis of patients with neurodegenerative disorders using NeuroX array

Ghani, Mahdi; Lang, Anthony E.; Zinman, Lorne; Nacmias, Benedetta; Sorbi, Sandro; Bessi, Valentina; Tedde, Andrea; Tartaglia, Maria Carmela; Surace, Ezequiel; Sato, Christine; Moreno, Danielle; Xi, Zhengrui; Hung, Rachel; Nalls, Mike A.; Singleton, Andrew B.; George-Hyslop, Peter St; Rogaeva, Ekaterina

doi:10.1016/j.neurobiolaging.2014.07.038

Cited by 41 publications

(37 citation statements)

References 40 publications

(36 reference statements)

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“…Although we did not observe the same extent of plaque accumulation in our APP transgenic mouse model as was seen in other studies (12), our findings support a role for ABCA7-mediated amyloid processing that may be working in combination with amyloid removal as factors for ABCA7 at-risk allelic variants. Recent studies have led to the identification of multiple ABCA7 coding variants that may also result in loss of function (62,63). It will be of considerable interest to determine the effects of these ABCA7 mutants on APP processing and A␤ clearance.…”

Section: Discussionmentioning

confidence: 99%

ATP-binding Cassette Transporter A7 (ABCA7) Loss of Function Alters Alzheimer Amyloid Processing

Satoh

Abe-Dohmae

Yokoyama

et al. 2015

Journal of Biological Chemistry

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106

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Background:The ATP-binding cassette transporter A7 (ABCA7) is a risk factor for sporadic Alzheimer disease (AD). Results: Loss of ABCA7 promoted A␤ processing and pathology in cell culture and AD mouse models. Conclusion: Altered ABCA7 function may contribute to AD by impacting A␤ production in addition to clearance. Significance: AD-related risk factors may contribute to disease progression through multiple pathways.The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late onset Alzheimer disease in genome-wide association studies. ABCA7 has been shown to mediate phagocytosis and affect membrane trafficking. The current study examined the impact of ABCA7 loss of function on amyloid precursor protein (APP) processing and generation of amyloid-␤ (A␤). Suppression of endogenous ABCA7 in several different cell lines resulted in increased ␤-secretase cleavage and elevated A␤. ABCA7 knock-out mice displayed an increased production of endogenous murine amyloid A␤42 species. Crossing ABCA7-deficient animals to an APP transgenic model resulted in significant increases in the soluble A␤ as compared with mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble A␤ and amyloid plaque densities were observed once the amyloid pathology was well developed, whereas A␤ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knock-out cells that is mechanistically consistent with the increased A␤ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing that may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to Alzheimer disease that in some instances have a greater impact than apoE allelic variants have recently been identified. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated Alzheimer disease susceptibility.Genome-wide association studies have identified the ATPbinding cassette transporter A7 (ABCA7) 2 as a susceptibility locus for late onset Alzheimer disease (LOAD) (1, 2). The single nucleotide polymorphisms (SNPs) associated with LOAD are distributed in various domains of the ABCA7 gene and include intronic SNPs and a coding sequence causing G1527A substitution. Studies have identified loci in different clusters, suggesting multiple sites within the ABCA7 gene associated with increased risk for AD (3). However, there is no indication that individuals with at-risk alleles display any differences in ABCA7 expression.ABCA7 is a member of the ATP-binding cassette transporter family largely involved in lipid transport and homeostasis (4). Its highly homologous member ABCA1 has also been linked to LOAD through cholesterol and processing of the amyloid precursor protein (5-7). Overexpression of ABCA7 resulted in a significant decrease in amyloid-...

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Section: Discussionmentioning

confidence: 99%

ATP-binding Cassette Transporter A7 (ABCA7) Loss of Function Alters Alzheimer Amyloid Processing

Satoh

Abe-Dohmae

Yokoyama

et al. 2015

Journal of Biological Chemistry

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106

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“…This was an exonic array (or exome chip) based on the Infinium Human Exome Beadchip v1.1 containing 242,901 exome-focused variants as well as 24,706 custom variants focusing on neurological diseases. The NeuroX array has already been successfully used in dozens of studies (Barber et al, 2017, Carrasquillo et al, 2016, Ghani et al, 2015, Nalls et al, 2016, Rosenthal et al, 2016). However, due to the backbone's focus on rare exonic variation, common non-exonic variants were largely missed, resulting in a modest genome-wide resolution and only partial capture of the known low frequency exonic variation.…”

Section: Introductionmentioning

confidence: 99%

NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases

Blauwendraat

Faghri

Pihlstrøm

et al. 2017

Neurobiology of Aging

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126

125

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Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array, and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases.

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“…However, in the last decade great advances have been made in our understanding of the pathogenetic mechanisms that lead to AD and PD [6–8]. It has been accepted that there are several genetic causes that play a role in the development of these disorders, including chromosome aberrations and gene mutations [8, 9]. Additionally, environmental exposures have been suggested to play a crucial role in the etiological process of neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review

et al. 2016

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ImportanceEpigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in neurodegenerative diseases (ND) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).ObjectiveTo systematically review studies investigating epigenetic marks in AD or PD.MethodsEleven bibliographic databases (Embase.com, Medline (Ovid), Web-of-Science, Scopus, PubMed, Cinahl (EBSCOhost), Cochrane Central, ProQuest, Lilacs, Scielo and Google Scholar) were searched until July 11th 2016 to identify relevant articles. We included all randomized controlled trials, cohort, case-control and cross-sectional studies in humans that examined associations between epigenetic marks and ND. Two independent reviewers, with a third reviewer available for disagreements, performed the abstract and full text selection. Data was extracted using a pre-designed data collection form.ResultsOf 6,927 searched references, 73 unique case-control studies met our inclusion criteria. Overall, 11,453 individuals were included in this systematic review (2,640 AD and 2,368 PD outcomes). There was no consistent association between global DNA methylation pattern and any ND. Studies reported epigenetic regulation of 31 genes (including cell communication, apoptosis, and neurogenesis genes in blood and brain tissue) in relation to AD and PD. Methylation at the BDNF, SORBS3 and APP genes in AD were the most consistently reported associations. Methylation of α-synuclein gene (SNCA) was also found to be associated with PD. Seven studies reported histone protein alterations in AD and PD.ConclusionMany studies have investigated epigenetics and ND. Further research should include larger cohort or longitudinal studies, in order to identify clinically significant epigenetic changes. Identifying relevant epigenetic changes could lead to interventional strategies in ND.

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Mutation analysis of patients with neurodegenerative disorders using NeuroX array

Cited by 41 publications

References 40 publications

ATP-binding Cassette Transporter A7 (ABCA7) Loss of Function Alters Alzheimer Amyloid Processing

ATP-binding Cassette Transporter A7 (ABCA7) Loss of Function Alters Alzheimer Amyloid Processing

NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases

The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review

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