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Mutations leading to premature termination codons in ATP-Binding Cassette Subfamily A Member 7 (ABCA7) are high penetrant risk factors of Alzheimer’s disease (AD). The influence of other genetic variants in ABCA7 and downstream functional mechanisms, however, is poorly understood. To address this knowledge gap, we investigated tandem repetitive regions in ABCA7 in a Belgian cohort of 1529 AD patients and control individuals and identified an intronic variable number tandem repeat (VNTR). We observed strong association between VNTR length and a genome-wide associated signal for AD in the ABCA7 locus. Expanded VNTR alleles were highly enriched in AD patients [odds ratio = 4.5 (1.3–24.2)], and VNTR length inversely correlated with amyloid β1–42 in cerebrospinal fluid and ABCA7 expression. In addition, we identified three novel ABCA7 alternative splicing events. One isoform in particular—which is formed through exon 19 skipping—lacks the first nucleotide binding domain of ABCA7 and is abundant in brain tissue. We observed a tight correlation between exon 19 skipping and VNTR length. Our findings underline the importance of studying repetitive DNA in complex disorders and expand the contribution of genetic and transcript variation in ABCA7 to AD.

Background The Alzheimer’s disease (AD) risk gene ABCA7 has suggested functions in lipid metabolism and the immune system. Rare premature termination codon (PTC) mutations and an expansion of a variable number of tandem repeats (VNTR) polymorphism in the gene, both likely cause a lower ABCA7 expression and hereby increased risk for AD. However, the exact mechanism of action remains unclear. By studying CSF biomarkers reflecting different types of AD-related pathological processes, we aim to get a better insight in those processes and establish a biomarker profile of mutation carriers. Methods The study population consisted of 229 AD patients for whom CSF was available and ABCA7 sequencing and VNTR genotyping had been performed. This included 28 PTC mutation and 16 pathogenic expansion carriers. CSF levels of Aβ 1–42 , Aβ 1–40 , P-tau 181 , T-tau, sAPPα, sAPPβ, YKL-40, and hFABP were determined using ELISA and Meso Scale Discovery assays. We compared differences in levels of these biomarkers and the Aβ ratio between AD patients with or without an ABCA7 PTC mutation or expansion using linear regression on INT-transformed data with APOE -status, age and sex as covariates. Results Carriers of ABCA7 expansion mutations had significantly lower Aβ 1–42 levels ( P  = 0.022) compared with non-carrier patients. The effect of the presence of ABCA7 mutations on CSF levels was especially pronounced in APOE ε4-negative carriers. In addition, VNTR expansion carriers had reduced Aβ 1–40 ( P  = 0.023), sAPPα ( P  = 0.047), sAPPβ ( P  = 0.016), and YKL-40 ( P  = 0.0036) levels. Conclusions Our results are suggestive for an effect on APP processing by repeat expansions given the changes in the amyloid-related CSF biomarkers that were found in carriers. The decrease in YKL-40 levels in expansion carriers moreover suggests that these patients potentially have a reduced inflammatory response to AD damage. Moreover, our findings suggest the existence of a mechanism, independent of lowered expression, affecting neuropathology in expansion carriers.

Mutations in CD59 cause CIDP-like polyneuropathy in children with inherited chronic hemolysis. We hypothesized that mutations in CD59 might be found in a subset of sporadic CIDP patients. 35 patients from two centers, fulfilling the EFNS/PNS diagnostic criteria for CIDP were included. CD59 coding region was amplified by PCR and Sanger sequenced. One rare variant was detected in a patient which resulted in a synonymous change and predicted to be neutral. Pathogenic variants were absent in our cohort. Our pilot study suggests that mutations in CD59 are absent in adult-onset sporadic CIDP.

[This corrects the article DOI: 10.1371/journal.pone.0212647.].

Alzheimer's disease (AD) is a growing problem worldwide. Since ABCA7’s identification as a risk gene, it has been extensively researched for its role in the disease. We review its recently characterized structure and what the mechanistic insights teach us about its function. We furthermore provide an overview of identified ABCA7 mutations, their presence in different ancestries and protein domains and how they might cause AD. For ABCA7 PTC variants and a VNTR expansion, haploinsufficiency is proposed as the most likely mode‐of‐action, although splice events could further influence disease risk. Overall, the need to better understand expression of canonical ABCA7 and its isoforms in disease is indicated. Finally, ABCA7's potential functions in lipid metabolism, phagocytosis, amyloid deposition, and the interplay between these three, is described. To conclude, in this review, we provide a comprehensive overview and discussion about the current knowledge on ABCA7 in AD, and what research questions remain. Highlights Alzheimer's risk‐increasing variants in ABCA7 can be found in up to 7% of AD patients. We review the recently characterized protein structure of ABCA7. We present latest insights in genetics, expression patterns, and functions of ABCA7.

Background ABCA7, an important risk gene for AD, encodes a transporter implicated in lipid transport and phagocytosis, and its disruptions have been linked to AD pathogenesis. However, the impact of these mutations on AD risk is complex due to their interaction with a multifaceted transcriptional architecture and cell type‐specificexpression patterns. This study aims to analyze the intricate patterns of ABCA7 expression across diverse cell types, considering various ABCA7 genotypes in relation to AD patients and non‐carrier controls, while also exploring the effects of ABCA7 mutations on transcriptome‐wide gene expression. Method To address this complexity, we performed droplet‐based single‐nuclei RNA sequencing on BA10 brain samples (ABCA7 mutation carriers [n = 9], non‐carrier AD patients [n = 6], and non‐carrier control [n = 8]) using 10x Chromium library preparation followed by sequencing on a NovaSeq6000 platform. Cell type annotation was performed using scSorter. Differential gene expression was analyzed using limma‐voom, and pathway analyses were performed using fgsea in R across cell types and studied groups. Result We obtained over 400,000 nuclei across 23 samples. Excitatory neurons had the highest proportion of cells expressing ABCA7. However, the highest average expression of ABCA7 was noted in microglia. We detected numerous differentially expressed genes between carrier and non‐carrier AD patients (pval_FDR_adj < 0.05 & abs(logFC) >1). Pathway analysis revealed a notable decrease in the expression of translation‐related genes in microglia, including those associated with nonsense‐mediated mRNA decay, in individuals carrying the mutation. Conclusion In conclusion, our study unveils distinctive patterns of ABCA7 expression and enriched pathways across major brain cell types, suggesting different roles of ABCA7 in different cell types.

ABCA7, an important risk gene for AD, encodes a transporter implicated in lipid transport and phagocytosis, and its disruptions have been linked to AD pathogenesis. However, the impact of these mutations on AD risk is complex due to their interaction with a multifaceted transcriptional architecture and cell type-specificexpression patterns. This study aims to analyze the intricate patterns of ABCA7 expression across diverse cell types, considering various ABCA7 genotypes in relation to AD patients and non-carrier controls, while also exploring the effects of ABCA7 mutations on transcriptome-wide gene expression. To address this complexity, we performed droplet-based single-nuclei RNA sequencing on BA10 brain samples (ABCA7 mutation carriers [n = 9], non-carrier AD patients [n = 6], and non-carrier control [n = 8]) using 10x Chromium library preparation followed by sequencing on a NovaSeq6000 platform. Cell type annotation was performed using scSorter. Differential gene expression was analyzed using limma-voom, and pathway analyses were performed using fgsea in R across cell types and studied groups. We obtained over 400,000 nuclei across 23 samples. Excitatory neurons had the highest proportion of cells expressing ABCA7. However, the highest average expression of ABCA7 was noted in microglia. We detected numerous differentially expressed genes between carrier and non-carrier AD patients (pval_FDR_adj < 0.05 & abs(logFC) >1). Pathway analysis revealed a notable decrease in the expression of translation-related genes in microglia, including those associated with nonsense-mediated mRNA decay, in individuals carrying the mutation. In conclusion, our study unveils distinctive patterns of ABCA7 expression and enriched pathways across major brain cell types, suggesting different roles of ABCA7 in different cell types.