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Human Molecular Genetics

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https://www.readbyqxmd.com/read/29452408/genome-wide-association-study-identifies-seven-novel-susceptibility-loci-for-primary-open-angle-glaucoma
#1
Yukihiro Shiga, Masato Akiyama, Koji M Nishiguchi, Kota Sato, Nobuhiro Shimozawa, Atsushi Takahashi, Yukihide Momozawa, Makoto Hirata, Matsuda Koichi, Taiki Yamaji, Motoki Iwasaki, Shoichiro Tsugane, Isao Oze, Haruo Mikami, Mariko Naito, Kenji Wakai, Munemitsu Yoshikawa, Masahiro Miyake, Kenji Yamashiro, Kenji Kashiwagi, Takeshi Iwata, Fumihiko Mabuchi, Mitsuko Takamoto, Mineo Ozaki, Kazuhide Kawase, Makoto Aihara, Makoto Araie, Tetsuya Yamamoto, Yoshiaki Kiuchi, Makoto Nakamura, Yasuhiro Ikeda, Koh-Hei Sonoda, Tatsuro Ishibashi, Koji Nitta, Aiko Iwase, Shiroaki Shirato, Yoshitaka Oka, Mamoru Satoh, Makoto Sasaki, Nobuo Fuse, Yoichi Suzuki, Ching-Yu Cheng, Chiea Chuen Khor, Mani Baskaran, Shamira Perera, Tin Aung, Eranga N Vithana, Jessica N Cooke Bailey, Jae H Kang, Louis R Pasquale, Jonathan L Haines, Janey L Wiggs, Kathryn P Burdon, Puya Gharahkhani, Alex W Hewitt, David A Mackey, Stuart MacGregor, Jamie E Craig, R Rand Allingham, Micheal Hauser, Adeyinka Ashaye, Donald L Budenz, Stephan Akafo, Susan E I Williams, Yoichiro Kamatani, Toru Nakazawa, Michiaki Kubo
Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7,378 POAG cases and 36,385 controls from a Japanese population. After combining the GWAS and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (p < 5...
February 14, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29452398/predominant-patterns-of-splicing-evolution-on-human-chimpanzee-and-macaque-evolutionary-lineages
#2
Jieyi Xiong, Jiang Xi, Angeliki Ditsiou, Yang Gao, Jing Sun, Elijah D Lowenstein, Shuyun Huang, Philipp Khaitovich
Although splicing is widespread and evolves rapidly among species, the mechanisms driving this evolution, as well as its functional implications, are not yet fully understood. We analyzed the evolution of splicing patterns based on transcriptome data from five tissues of humans, chimpanzees, rhesus macaques, and mice. In total, 1,526 exons and exon sets from 1,236 genes showed significant splicing differences among primates. More than 60% of these differences represent constitutive-to-alternative exon transitions while an additional 25% represent changes in exon inclusion frequency...
February 14, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29452354/alpha-synuclein-inhibits-snx3-retromer-mediated-retrograde-recycling-of-iron-transporters-in-s-cerevisiae-and-c-elegans-models-of-parkinson-s-disease
#3
Dhaval Patel, Chuan Xu, Sureshbabu Nagarajan, Zhengchang Liu, Wayne O Hemphill, Runhua Shi, Vladimir N Uversky, Guy A Caldwell, Kim A Caldwell, Stephan N Witt
We probed the role of alpha-synuclein (α-syn) in modulating sorting nexin 3 (Snx3)-retromer-mediated recycling of iron transporters in Saccharomyces cerevisiae and Caenorhabditis elegans. In yeast, the membrane-bound heterodimer Fet3/Ftr1 is the high affinity iron importer. Fet3 is a membrane-bound multicopper ferroxidase, whose ferroxidase domain is orthologous to human ceruloplasmin (Cp), that oxidizes external Fe+2 to Fe+3; the Fe+3 ions then channel through the Ftr1 permease into the cell. When the concentration of external iron is low (< 1 µM), Fet3/Ftr1 is maintained on the plasma membrane by retrograde endocytic-recycling; whereas, when the concentration of external iron is high (> 10 µM), Fet3/Ftr1 is endocytosed and shunted to the vacuole for degradation...
February 14, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29452352/conditional-ablation-and-conditional-rescue-models-for-casq2-elucidate-the-role-of-development-and-of-cell-type-specific-expression-of-casq2-in-the-cpvt2-phenotype
#4
Daniel J Flores, ThuyVy Duong, Luke O Brandenberger, Apratim Mitra, Aditya Shirali, John C Johnson, Danielle Springer, Audrey Noguchi, Zu-Xi Yu, Steven N Ebert, Andreas Ludwig, Bjorn C Knollmann, Mark D Levin, Karl Pfeifer
Cardiac calsequestrin (Casq2) associates with the Ryanodine Receptor 2 channel in the junctional sarcoplasmic reticulum to regulate Ca2+ release into the cytoplasm. Patients carrying mutations in CASQ2 display low resting heart rates under basal conditions and stress-induced polymorphic ventricular tachycardia (CPVT). In this study we generate and characterize novel conditional deletion and conditional rescue mouse models to test the influence of developmental programs on the heart rate and CPVT phenotypes...
February 14, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29447355/a-recurrent-de-novo-missense-mutation-in-ubtf-causes-developmental-neuroregression
#5
Camilo Toro, Roderick T Hori, May Christine V Malicdan, Cynthia J Tifft, Amy Goldstein, William A Gahl, David R Adams, Harper B Fauni, Lynne A Wolfe, Jianfeng Xiao, Mohammad M Khan, Jun Tian, Kevin A Hope, Lawrence T Reiter, Michel G Tremblay, Tom Moss, Alexis L Franks, Chris Balak, Mark S LeDoux
No abstract text is available yet for this article.
February 13, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29447348/transcriptome-analysis-reveals-intermittent-fasting-induced-genetic-changes-in-ischemic-stroke
#6
Joonki Kim, Sung-Wook Kang, Karthik Mallilankaraman, Sang-Ha Baik, James C Lim, Priyanka Balaganapathy, David T She, Ker-Zhing Lok, David Y Fann, Uma Thambiayah, Sung-Chun Tang, Alexis M Stranahan, S Thameem Dheen, Mathias Gelderblom, Raymond C Seet, Vardan T Karamyan, Raghu Vemuganti, Christopher G Sobey, Mark P Mattson, Dong-Gyu Jo, Thiruma V Arumugam
Genetic changes due to dietary intervention in the form of either calorie restriction (CR) or intermittent fasting (IF) are not reported in detail until now. However, it is well established that both CR and IF extend the lifespan and protect against neurodegenerative diseases and stroke. The current research aims were first to describe the transcriptomic changes in brains of IF mice and, second, to determine whether IF induces extensive transcriptomic changes following ischemic stroke to protect the brain from injury...
February 13, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29438482/the-lipodystrophic-hotspot-lamin-a-p-r482w-mutation-deregulates-the-mesodermal-inducer-t-brachyury-and-early-vascular-differentiation-gene-networks
#7
Nolwenn Briand, Anne-Claire Guénantin, Dorota Jeziorowska, Akshay Shah, Matthieu Mantecon, Emilie Capel, Marie Garcia, Anja Oldenburg, Jonas Paulsen, Jean-Sebastien Hulot, Corinne Vigouroux, Philippe Collas
The p.R482W hotspot mutation in A-type nuclear lamins causes familial partial lipodystrophy of Dunnigan-type (FPLD2), a lipodystrophic syndrome complicated by early-onset atherosclerosis. Molecular mechanisms underlying endothelial cell dysfunction conferred by the lamin A mutation remain elusive. However, lamin A regulates epigenetic developmental pathways and mutations could perturb these functions. Here, we demonstrate that lamin A R482W elicits endothelial differentiation defects in a developmental model of FPLD2...
February 9, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29432581/14q32-and-let-7-micrornas-regulate-transcriptional-networks-in-fetal-and-adult-human-erythroblasts
#8
Samuel Lessard, Mélissa Beaudoin, Stuart H Orkin, Daniel E Bauer, Guillaume Lettre
In humans, fetal erythropoiesis takes place in the liver whereas adult erythropoiesis occurs in the bone marrow. Fetal and adult erythroid cells are not only produced at different sites, but are also distinguished by their respective transcriptional program. In particular, whereas fetal erythroid cells express γ-globin chains to produce fetal hemoglobin (HbF), adult cells express β-globin chains to generate adult hemoglobin. Understanding the transcriptional regulation of the fetal-to-adult hemoglobin switch is clinically important as re-activation of HbF production in adult erythroid cells would represent a promising therapy for the hemoglobin disorders sickle cell disease and β-thalassemia...
February 8, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29432577/sema3a-plays-a-role-in-the-pathogenesis-of-charge-syndrome
#9
Roser Ufartes, Janina Schwenty-Lara, Luisa Freese, Christiane Neuhofer, Janika Möller, Peter Wehner, Conny M A van Ravenswaaij-Arts, Monica T Y Wong, Ina Schanze, Andreas Tzschach, Oliver Bartsch, Annette Borchers, Silke Pauli
CHARGE syndrome is an autosomal dominant malformation disorder caused by heterozygous loss of function mutations in the chromatin remodeler CHD7. Chd7 regulates the expression of Sema3a, which also contributes to the pathogenesis of Kallmann syndrome, a heterogeneous condition with the typical features hypogonadotropic hypogonadism and an impaired sense of smell. Both features are common in CHARGE syndrome suggesting that SEMA3A may provide a genetic link between these syndromes. Indeed, we find evidence that SEMA3A plays a role in the pathogenesis of CHARGE syndrome...
February 8, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29432563/traumatic-injury-induces-stress-granule-formation-and-enhances-motor-dysfunctions-in-als-ftd-models
#10
Eric N Anderson, Lauren Gochenaur, Aditi Singh, Rogan Grant, Krishani Patel, Simon Watkins, Jane Y Wu, Udai Bhan Pandey
Traumatic brain injury (TBI) has been predicted to be a predisposing factor for Amyotrophic lateral sclerosis (ALS) and other neurological disorders. Despite the importance of TBI in ALS progression, the underlying cellular and molecular mechanisms are still an enigma. Here, we examined the contribution of TBI as an extrinsic factor and investigated if TBI influences the susceptibility of developing neurodegenerative symptoms. To evaluate the effects of TBI in vivo, we applied mild to severe trauma to Drosophila and found that TBI leads to the induction of stress granules (SGs) in the brain...
February 8, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29432562/loss-of-function-and-gain-of-function-mutations-in-ppp3ca-cause-two-distinct-disorders
#11
Takeshi Mizuguchi, Mitsuko Nakashima, Mitsuhiro Kato, Nobuhiko Okamoto, Hirokazu Kurahashi, Nina Ekhilevitch, Masaaki Shiina, Gen Nishimura, Takashi Shibata, Muneaki Matsuo, Tae Ikeda, Kazuhiro Ogata, Naomi Tsuchida, Satomi Mitsuhashi, Satoko Miyatake, Atsushi Takata, Noriko Miyake, Kenichiro Hata, Tadashi Kaname, Yoichi Matsubara, Hirotomo Saitsu, Naomichi Matsumoto
Calcineurin is a calcium (Ca2+)/calmodulin-regulated protein phosphatase that mediates Ca2+-dependent signal transduction. Here, we report six heterozygous mutations in a gene encoding the alpha isoform of the calcineurin catalytic subunit (PPP3CA). Notably, mutations were observed in different functional domains: in addition to three catalytic domain mutations, two missense mutations were found in the auto-inhibitory (AI) domain. One additional frameshift insertion that caused premature termination was also identified...
February 8, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29432535/protein-kinase-c-activity-is-a-protective-modifier-of-purkinje-neuron-degeneration-in-cerebellar-ataxia
#12
Ravi Chopra, Aaron H Wasserman, Stefan M Pulst, Chris I De Zeeuw, Vikram G Shakkottai
Among the many types of neurons expressing protein kinase C (PKC) enzymes, cerebellar Purkinje neurons are particularly reliant on appropriate PKC activity for maintaining homeostasis. The importance of PKC enzymes in Purkinje neuron health is apparent as mutations in PRKCG (encoding PKCγ) cause cerebellar ataxia. PRKCG has also been identified as an important node in ataxia gene networks more broadly, but the functional role of PKC in other forms of ataxia remains unexplored, and the mechanisms by which PKC isozymes regulate Purkinje neuron health are not well understood...
February 8, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29432529/the-pro-apoptotic-jnk-scaffold-posh-sh3rf1-mediates-chmp2bintron5-associated-toxicity-in-animal-models-of-frontotemporal-dementia
#13
Ryan J H West, Chris Ugbode, Fen-Biao Gao, Sean T Sweeney
Frontotemporal Dementia (FTD) is one of the most prevalent forms of early-onset dementia. However, the pathological mechanisms driving neuronal atrophy in FTD remain poorly understood. Here we identify a conserved role for the novel pro-apoptotic protein POSH/SH3RF1 in mediating neuropathology in Drosophila and mammalian models of CHMP2BIntron5associated FTD. Aberrant, AKT dependent, accumulation of POSH was observed throughout the nervous system of both Drosophila and mice expressing CHMP2BIntron5. Knockdown of POSH was shown to be neuroprotective and sufficient to alleviate aberrant neuronal morphology, behavioral deficits and premature-lethality in Drosophila models, as well as dendritic collapse and cell death in CHMP2BIntron5expressing rat primary neurons...
February 8, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29425337/self-assembly-of-fus-through-its-low-complexity-domain-contributes-to-neurodegeneration
#14
Taisei Matsumoto, Koji Matsukawa, Naruaki Watanabe, Yuya Kishino, Hayato Kunugi, Ryoko Ihara, Tomoko Wakabayashi, Tadafumi Hashimoto, Takeshi Iwatsubo
Aggregation of fused in sarcoma (FUS) protein, and mutations in FUS gene, are causative to a range of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. To gain insights into the molecular mechanism whereby FUS causes neurodegeneration, we generated transgenic Drosophila melanogaster overexpressing human FUS in the photoreceptor neurons, which exhibited mild retinal degeneration. Expression of familial ALS-mutant FUS aggravated the degeneration, which was associated with an increase in cytoplasmic localization of FUS...
February 7, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29415125/elongator-subunit-3-elp3-modifies-als-through-trna-modification
#15
Andre Bento-Abreu, Gunilla Jager, Bart Swinnen, Laura Rué, Stijn Hendrickx, Ashley Jones, Kim A Staats, Ines Taes, Caroline Eykens, Annelies Nonneman, Rik Nuyts, Mieke Timmers, Lara Silva, Alain Chariot, Laurent Nguyen, John Ravits, Robin Lemmens, Deirdre Cabooter, Van Den Bosch Ludo, Philip Van Damme, Ammar Al-Chalabi, Anders Bystrom, Wim Robberecht
Amyotrophic Lateral Sclerosis (ALS) is a fatal degenerative motor neuron disorder of which the progression is influenced by several disease-modifying factors. Here, we investigated ELP3, a subunit of the elongator complex that modifies tRNA wobble uridines, as one of such ALS disease modifiers. ELP3 attenuated the axonopathy of a mutant SOD1, as well as of a mutant C9orf72 ALS zebrafish model. Furthermore, expression of ELP3 in the SOD1G93A mouse extended the survival and attenuated the denervation in this model...
February 3, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29409023/erp57-is-protective-against-mutant-sod1-induced-cellular-pathology-in-amyotrophic-lateral-sclerosis
#16
Sonam Parakh, Cyril J Jagaraj, Marta Vidal, Audrey M G Ragagnin, Emma R Perri, Anna Konopka, Reka Toth, Jasmin Galper, Ian P Blair, Colleen J Thomas, Adam K Walker, Shu Yang, Damian M Spencer, Julie D Atkin
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and mutations in superoxide dismutase1 (SOD1) account for 20% of familial ALS cases. The aetiology of ALS remains unclear, but protein misfolding, endoplasmic reticulum (ER) stress and neuronal apoptosis are implicated. We previously established that protein disulphide isomerase (PDIA1) is protective against ER stress and apoptosis in neuronal cells expressing mutant SOD1, recently mutations in PDIA1 and related PDI family member endoplasmic reticulum protein 57 (ERp57/PDIA), were associated with ALS...
February 1, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29408999/hippocampal-mutant-app-and-amyloid-beta-induced-cognitive-decline-dendritic-spine-loss-defective-autophagy-mitophagy-and-mitochondrial-abnormalities-in-a-mouse-model-of-alzheimer-s-disease
#17
Maria Manczak, Ramesh Kandimalla, Xiangling Yin, P Hemachandra Reddy
The purpose of our study was to determine the toxic effects of hippocampal mutant APP and amyloid beta (Aβ) in 12-month-old APP transgenic mice. Using rotarod and Morris Water Maze tests, immunoblotting & immunofluorescence, Golgi-cox staining and transmission electron microscopy, we assessed cognitive behavior, protein levels of synaptic, autophagy, mitophagy, mitochondrial dynamics, biogenesis, dendritic protein MAP2, and quantified dendritic spines and mitochondrial number and length in 12-month-old APP mice that express swedish mutation...
February 1, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29408991/astrocytes-new-players-in-progressive-myoclonus-epilepsy-of-lafora-type
#18
Carla Rubio-Villena, Rosa Viana, Jose Bonet, Maria Adelaida Garcia-Gimeno, Marta Casado, Miguel Heredia, Pascual Sanz
Lafora disease (LD) is a fatal form of progressive myoclonus epilepsy characterized by the accumulation of insoluble poorly branched glycogen-like inclusions named Lafora bodies (LBs) in the brain and peripheral tissues. In the brain, since its first discovery in 1911, it was assumed that these glycogen inclusions were only present in affected neurons. Mouse models of LD have been obtained recently, and we and others have been able to report the accumulation of glycogen inclusions in the brain of LD animals, what recapitulates the hallmark of the disease...
February 1, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29401312/differentially-expressed-micrornas-in-the-aqueous-humor-of-patients-with-exfoliation-glaucoma-or-primary-open-angle-glaucoma
#19
Michelle D Drewry, Pratap Challa, John G Kuchtey, Iris Navarro, Inas Helwa, Yanzhong Hu, Hongmei Mu, W Daniel Stamer, Rachel W Kuchtey, Yutao Liu
Both exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) have been linked to decreased conventional outflow of aqueous humor (AH). To better understand the molecular changes in the AH content under such conditions, we analyzed the miRNA profiles of AH samples from patients with POAG and XFG compared to non-glaucoma controls. Individual AH samples (n = 76) were collected from POAG and XFG patients and age-matched controls during surgical procedure. After RNA extraction, the miRNA profiles were individually determined in 12 POAG, 12 XFG, and 11 control samples...
February 1, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29401310/human-cis-acting-elements-regulating-escape-from-x-chromosome-inactivation-function-in-mouse
#20
Samantha B Peeters, Andrea J Korecki, Elizabeth M Simpson, Carolyn J Brown
A long-standing question concerning X-chromosome inactivation (XCI) has been how some genes avoid the otherwise stable chromosome-wide heterochromatinization of the inactive X chromosome. As 20% or more of human X-linked genes escape from inactivation, such genes are an important contributor to sex differences in gene expression. Although both human and mouse have genes that escape from XCI, more genes escape in humans than mice, with human escape genes often clustering in larger domains than the single escape genes of mouse...
February 1, 2018: Human Molecular Genetics
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