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Epigenetic Alterations in Alzheimer’s Disease and Its Therapeutic and Dietary Interventions
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
P. M. Aswathy, C. M. Shafeeque, Moinak Banerjee
An investigation of the methylation status of DNA repair genes in AD subjects, compared with controls, did not find any increased promoter methylation in peripheral blood of AD patients (Coppedè et al. 2017). A cross-tissue analysis of methylomic variation in AD, using samples from four independent human post-mortem brain cohorts, identified a differentially hypermethylated region in the Ankyrin 1 (ANK1) gene, that was associated with neuropathology in the entorhinal cortex (and also in the superior temporal gyrus and prefrontal cortex), the primary site of AD manifestation (Lunnon et al. 2014). A dynamic regulation of DNA methylation in the human cerebral cortex has been reported throughout the lifespan, with hypermethylation of vinexin (encoding a cell adhesion molecule expressed in neurons and glia) (Ito et al. 2007) and hypomethylation of S100A2 (a member of the S100 family of calcium-binding proteins), compared with other non-AD subjects older than 60 years (Siegmund et al. 2007). Hypomethylation of CREB5, encoding a transcription factor implicated in synaptic plasticity and cognition, was reported in the prefrontal cortex from AD and normal subjects (Zukin 2009). Hypomethylation of the mitochondrial DNA (mtDNA) D-loop region was reported in peripheral blood DNA of LOAD patients (Stoccoro et al. 2017). Another study reported hypermethylation in the opioid receptor delta 1 (OPRD1, a member of the opioid family of G-protein-coupled receptors) promoter region, and discussed its role in influencing the risk of AD.
The Epigenetic Role of Vitamin C in Neurological Development and Disease
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
The epigenetic determinants surrounding AD are complex, and the role that DNA methylation/demethylation plays seems equivocal. Many studies have shown that methylation dynamics are disrupted in AD patient brains, although the exact effect this has on disease states is unclear. Increased methylation of ABCA7, BIN1, ANK1, and other AD susceptibility genes is associated with increased AD pathology burden [93]. This association was also observed in methylation of the HOXA gene cluster and can most likely be found in other neurodevelopmental genes [94]. Conversely, other studies have reported global decreases in 5mC in patient brain entorhinal cortex that negatively correlate with Aβ hippocampal load [95,96]. Work investigating 5hmC content in AD patient brains has been similarly ambiguous. Some studies have reported decreased 5hmC content in AD patient entorhinal cortex and cerebellum, while others have found increased 5hmC content in AD middle frontal gyrus and a positive correlation between 5hmC and AD pathology [95–99]. These discrepancies could be due to differences in the age of patients from which diseased brain tissue was derived. AD is a progressive multistage disease of aging, and methylation profiles could conceivably change between consecutive stages of disease severity. Furthermore, these studies examined brain tissue from a variety of brain regions, and there is little reason to believe that methylation profiles are similar between these regions. This variability in patient age and tissue selection could explain inconsistencies in the literature and furthermore confound interpretation of promising findings. Despite the lack of a clear-cut understanding regarding methylation and AD etiology, it is plausible that dysregulation of methylation dynamics may underlie disease onset and severity. More work is needed to examine the role of 5mC and 5hmC in disease pathology and whether the neuroprotective role of vitamin C in AD is mediated by its function in regulating these marks.
Targeted next-generation sequencing identified a novel ANK1 mutation associated with hereditary spherocytosis in a Chinese family
Published in Hematology, 2019
Qing Sun, Yao Xie, Penghui Wu, Shuo Li, Ying Hua, Xintian Lu, Weihong Zhao
HS represents a group of congenital diseases characterized by the presence of spherical erythrocytes in peripheral blood smears [12]. Moreover, HS is the most common cause of congenital haemolytic anaemia due to membrane protein defects [13]. The ANK1 gene is located on chromosome 8p11.1 and encodes several alternatively spliced isoforms [14]. Erythroid ankyrin is the predominant protein encoded by ANK1 in red blood cells. Because ankyrin attaches β-spectrin to the band 3 protein, lack of ankyrin leads to a proportional and secondary decrease in spectrin assembly on the membrane, in spite of normal spectrin synthesis [15]. Defects in these proteins lead to a decrease in the erythrocyte surface area, a spherical shape of erythrocytes and, in particular, loss of membrane elasticity and mechanical stability [16].
Screening tools for hereditary hemolytic anemia: new concepts and strategies
Published in Expert Review of Hematology, 2021
Elisa Fermo, Cristina Vercellati, Paola Bianchi
Since traditional Sanger sequencing is relatively expensive and time-consuming, DNA analysis has historically been the last step of the diagnostic workflow of hereditary hemolytic anemias, or even not considered, as in the case of HS, due to the high number and size of involved genes (ANK1, SPTA1, SPTB, SLC4A1, EBP42, EPB41) and the high number of pathogenic variants detected that are mostly private; in addition, depending on the aminoacidic position in the protein or on genetic transmission, variants in genes encoding for RBC cytoskeleton may result in different phenotypes (for example mutations in SPTA1 may be associated to HS, HE, or HPP, or mutations in SLC4A1 may cause HS, South East Asian Ovalocytosis, stomatocytic forms or renal tubular acidosis).
Identification of a de novo ANK1 mutation in a Chinese family with hereditary spherocytosis
Published in Hematology, 2018
Hongzai Guan, Xinping Liang, Rong Zhang, Haiyan Wang, Wenmiao Liu, Ru Zhang, Jie Yang, Shiguo Liu
ANK1 mutation is the most common cause of typical dominant HS [8], accounting for about half of HS patients. ANK1, located on chromosome 8p11.2, encodes erythroid ankyrin 1 [9] which is an important red cell membrane protein that interacts with transmembrane proteins and the membrane skeleton of cells through spectrin, band 3, and band 4.2 proteins. In most cases, HS patients carrying different ANK1 mutations such as the nonsense, splicing or frameshift mutations have a complex relationship between genotype and phenotype due to genetic heterogeneity.