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Human Molecular Genetics

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https://www.readbyqxmd.com/read/29688516/transcriptome-analysis-reveals-intermittent-fasting-induced-genetic-changes-in-ischemic-stroke
#1
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
No abstract text is available yet for this article.
April 24, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29688489/protective-role-of-the-lipid-phosphatase-fig4-in-the-adult-nervous-system
#2
Yevgeniya A Mironova, Jing-Ping Lin, Ashley Kalinski, Lucas Huffman, Guy M Lenk, Leif A Havton, Miriam H Meisler, Roman J Giger
The signaling lipid phosphatidylinositol 3,5-bisphosphate, PI(3,5)P2, functions in vesicular trafficking through the endo-lysosomal compartment. Cellular levels of PI(3,5)P2 are regulated by an enzyme complex comprised of the kinase PIKFYVE, the phosphatase FIG4, and the scaffold protein VAC14. Mutations of human FIG4 cause inherited disorders including Charcot-Marie-Tooth disease type 4J, polymicrogyria with epilepsy, and Yunis-Varón syndrome. Constitutive Fig4-/- mice exhibit intention tremor, spongiform degeneration of neural tissue, hypomyelination, and juvenile lethality...
April 24, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29688405/a-homozygous-mutation-p-arg2167trp-in-frem2-causes-isolated-cryptophthalmos
#3
Qian Yu, Bingying Lin, Shangqian Xie, Song Gao, Wei Li, Yizhi Liu, Hongwei Wang, Danping Huang, Zhi Xie
Cryptophthalmos (CO, MIM: 123570) is rare congenital anomalies of eyelid formation, which can occur alone or in combination with multiple congenital anomalies as part of Fraser syndrome (FS) or Manitoba Oculotrichoanal (MOTA) syndrome. Causal mutations have been identified for these syndromes but not in the isolated cases. Here, we described two patients from two unrelated Chinese families: one with unilateral isolated CO, while the other with unilateral CO and renal agenesis. A novel homozygous mutation (c...
April 24, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29688390/tripolar-chromosome-segregation-drives-the-association-between-maternal-genotype-at-variants-spanning-plk4-and-aneuploidy-in-human-preimplantation-embryos
#4
Rajiv C McCoy, Louise J Newnham, Christian S Ottolini, Eva R Hoffmann, Katerina Chatzimeletiou, Omar E Cornejo, Qiansheng Zhan, Nikica Zaninovic, Zev Rosenwaks, Dmitri A Petrov, Zachary P Demko, Styrmir Sigurjonsson, Alan H Handyside
Aneuploidy is prevalent in human embryos and is the leading cause of pregnancy loss. Many aneuploidies arise during oogenesis, increasing with maternal age. Superimposed on these meiotic aneuploidies are frequent errors occurring during early mitotic divisions, contributing to widespread chromosomal mosaicism. Here we reanalyzed a published dataset comprising preimplantation genetic testing for aneuploidy in 24,653 blastomere biopsies from day-3 cleavage-stage embryos, as well as 17,051 trophectoderm biopsies from day-5 blastocysts...
April 24, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29688337/stimulation-of-s1pr5-with-a-971432-a-selective-agonist-preserves-blood-brain-barrier-integrity-and-exerts-therapeutic-effect-in-an-animal-model-of-huntington-s-disease
#5
Alba Di Pardo, Salvatore Castaldo, Enrico Amico, Giuseppe Pepe, Federico Marracino, Luca Capocci, Alfredo Giovannelli, Michele Madonna, Jeroen van Bergeijk, Fabio Buttari, Elizabeth van der Kam, Vittorio Maglione
Huntington's disease (HD) is the most common neurodegenerative disorder for which no effective cure is yet available. Although several agents have been identified to provide benefits so far, the number of therapeutic options remains limited with only symptomatic treatment available. Over the past few years, we have demonstrated that sphingolipid-based approaches may open the door to new and more targeted treatments for the disease.In this study, we investigated the therapeutic potential of stimulating Sphingosine-1-phosphate (S1P) receptor 5 by the new selective agonist A-971432 (provided by AbbVie) in R6/2 mice, a widely-used HD animal model...
April 24, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29684205/neurodegenerative-diseases-have-genetic-hallmarks-of-autoinflammatory-disease
#6
Robert I Richards, Sarah A Robertson, Daniel L Kastner
The notion that one common pathogenic pathway could account for the various clinically distinguishable, typically late-onset neurodegenerative diseases might appear unlikely given the plethora of diverse primary causes of neurodegeneration. On the contrary, an autoinflammatory pathogenic mechanism allows diverse genetic and environmental factors to converge into a common chain of causality. Inflammation has long been known to correlate with neurodegeneration. Until recently this relationship was seen as one of consequence rather than cause - with inflammatory cells and events acting to "clean up the mess" after neurological injury...
April 19, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29672687/the-big-data-revolution-and-human-genetics
#7
Nicholas J Schork
No abstract text is available yet for this article.
April 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29668946/a-system-biology-perspective-on-environment-host-microbe-interactions
#8
Lianmin Chen, Sanzhima Garmaeva, Alexandra Zherankova, Jingyuan Fu, Cisca Wijmenga
A vast, complex and dynamic consortium of microorganisms known as the gut microbiome colonizes the human gut. Over the past few decades we have developed an increased awareness of its important role in human health. In this review we discuss the role of the gut microbiome in complex diseases and the possible causal scenarios behind its interactions with the host genome and environmental factors. We then propose a new analysis framework that combines a systems biology approach, cross-kingdom integration of multiple levels of omics data, and innovative in vitro models to yield an integrated picture of human host-microbe interactions...
April 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29668927/elevated-dual-specificity-protein-phosphatase-4-in-cardiomyopathy-caused-by-lamin-a-c-gene-mutation-is-primarily-erk1-2-dependent-and-its-depletion-improves-cardiac-function-and-survival
#9
Jason C Choi, Wei Wu, Elizabeth Phillips, Robin Plevin, Fusako Sera, Shunichi Homma, Howard J Worman
Mutations in the lamin A/C gene (LMNA) encoding the nuclear intermediate filament proteins lamins A and C cause a group of tissue-selective diseases, the most common of which is dilated cardiomyopathy (herein referred to as LMNA cardiomyopathy) with variable skeletal muscle involvement. We previously showed that cardiomyocyte-specific overexpression of dual specificity protein phosphatase 4 (DUSP4) is involved in the pathogenesis of LMNA cardiomyopathy. However, how mutations in LMNA activate Dusp4 expression and whether it is necessary for the development of LMNA cardiomyopathy are currently unknown...
April 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29668904/a-whole-brain-longitudinal-study-in-the-yac128-mouse-model-of-huntington-s-disease-shows-distinct-trajectories-of-neurochemical-structural-connectivity-and-volumetric-changes
#10
Lorena I Petrella, João M Castelhano, Mario Ribeiro, José V Sereno, Sónia I Gonçalves, Mário N Laço, Michael R Hayden, Ana C Rego, Miguel Castelo-Branco
Huntington's disease (HD) is a neurodegenerative disorder causing cognitive and motor impairments, evolving to death within 15-20 years after symptom onset. We previously established a mouse model with the entire human HD gene containing 128 CAG repeats (YAC128) which accurately recapitulates the natural history of the human disease. Defined time points in this natural history enable the understanding of longitudinal trajectories from the neurochemical and structural points of view using non-invasive high-resolution multimodal imaging...
April 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29668892/sumoylation-of-xrcc1-activated-by-poly-adp-ribosyl-ation-regulates-dna-repair
#11
Ling-Yueh Hu, Che-Chang Chang, Yen-Sung Huang, Wen-Cheng Chou, Ying-Mei Lin, Chun-Chen Ho, Wei-Ting Chen, Hsiu-Ming Shih, Chia-Ni Hsiung, Pei-Ei Wu, Chen-Yang Shen
XRCC1 is an essential scaffold protein for base excision repair (BER) and helps to maintain genomic stability. XRCC1 has been indicated as a substrate for small ubiquitin-like modifier modification (SUMOylation); however, how XRCC1 SUMOylation is regulated in cells and how SUMOylated XRCC1 regulates BER activity are not well understood. Here we show that SUMOylation of XRCC1 is regulated in cells under methyl-methanesulfonate (MMS) treatment and facilitates BER. Poly(ADP-ribose) polymerase 1 (PARP1) is activated by MMS immediately and synthesizes poly(ADP-ribose) (PAR), which in turn promotes recruitment of SUMO E3 TOPORS to XRCC1 and facilitates XRCC1 SUMOylation...
April 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29659842/insights-into-the-pathogenesis-of-dominant-retinitis-pigmentosa-associated-with-a-d477g-mutation-in-rpe65
#12
Elliot H Choi, Susie Suh, Christopher L Sander, Christian J Ortiz Hernandez, Elizabeth R Bulman, Nimesh Khadka, Zhiqian Dong, Wuxian Shi, Krzysztof Palczewski, Philip D Kiser
RPE65 is the essential trans-cis isomerase of the classical retinoid (visual) cycle. Mutations in RPE65 give rise to severe retinal dystrophies, most of which are associated with loss of protein function and recessive inheritance. The only known exception is a c.1430G>A (D477G) mutation that gives rise to dominant retinitis pigmentosa with delayed onset and choroidal and macular involvement. Position 477 is distant from functionally critical regions of RPE65. Hence, the mechanism of D477G pathogenicity remains unclear, although protein misfolding and aggregation mechanisms have been suggested...
April 12, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29659838/comparative-methylome-analysis-of-icf-patients-identifies-heterochromatin-loci-that-require-zbtb24-cdca7-and-hells-for-their-methylated-state
#13
Guillaume Velasco, Giacomo Grillo, Nizar Touleimat, Laure Ferry, Ivana Ivkovic, Florence Ribierre, Jean-François Deleuze, Sophie Chantalat, Capucine Picard, Claire Francastel
Alterations of DNA methylation landscapes and machinery are a hallmark of many human diseases. A prominent case is the ICF syndrome, a rare autosomal recessive immunological/neurological disorder diagnosed by the loss of DNA methylation at (peri)centromeric repeats and its associated chromosomal instability. It is caused by mutations in the de novo DNA methyltransferase DNMT3B in about half of the patients (ICF1). In the remainder, the striking identification of mutations in factors devoid of DNA methyltransferase activity, ZBTB24 (ICF2), CDCA7 (ICF3) or HELLS (ICF4), raised key questions about common or distinguishing DNA methylation alterations downstream of these mutations and hence, about the functional link between the four factors...
April 12, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29659837/noonan-syndrome-causing-shp2-mutants-impair-erk-dependent-chondrocyte-differentiation-during-endochondral-bone-growth
#14
Mylène Tajan, Julie Pernin-Grandjean, Nicolas Beton, Isabelle Gennero, Florence Capilla, Benjamin G Neel, Toshiyuki Araki, Philippe Valet, Maithé Tauber, Jean-Pierre Salles, Armelle Yart, Thomas Edouard
Growth retardation is a constant feature of Noonan syndrome (NS) but its physiopathology remains poorly understood. We previously reported that hyperactive NS-causing SHP2 mutants impair the systemic production of insulin-like growth factor 1 (IGF1) through hyperactivation of the RAS/extracellular signal-regulated kinases (ERK) signalling pathway. Besides endocrine defects, a direct effect of these mutants on growth plate has not been explored, although recent studies have revealed an important physiological role for SHP2 in endochondral bone growth...
April 12, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29659830/genome-wide-association-study-identifies-nine-novel-loci-for-2d-4d-finger-ratio-a-putative-retrospective-biomarker-of-testosterone-exposure-in-utero
#15
Nicole M Warrington, Enisa Shevroja, Gibran Hemani, Pirro G Hysi, Yunxuan Jiang, Adam Auton, Cindy G Boer, Massimo Mangino, Carol A Wang, John P Kemp, George McMahon, Carolina Medina-Gomez, Martha Hickey, Katerina Trajanoska, Dieter Wolke, Arfan M Ikram, Grant W Montgomery, Janine F Felix, Margaret J Wright, David A Mackey, Vincent W Jaddoe, Nicholas G Martin, Joyce Y Tung, George Davey Smith, Craig E Pennell, Tim D Spector, Joyce van Meurs, Fernando Rivadeneira, Sarah E Medland, David M Evans
The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a noninvasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sex-specific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N = 15,661, with replication N = 75,821), we identified eleven loci (nine novel) explaining 3...
April 12, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29659828/the-next-generation-of-precision-medicine-observational-studies-electronic-health-records-biobanks-and-continuous-monitoring
#16
Benjamin S Glicksberg, Kipp W Johnson, Joel T Dudley
Precision medicine can utilize new techniques in order to more effectively translate research findings into clinical practice. In this article, we first explore the limitations of traditional study designs, which stem from (to name a few): massive cost for the assembly of large patient cohorts; non-representative patient data; and the astounding complexity of human biology. Second, we propose that harnessing electronic health records and mobile device biometrics coupled to longitudinal data may prove to be a solution to many of these problems by capturing a "real world" phenotype...
April 12, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29659825/differential-effects-of-14-3-3-dimers-on-tau-phosphorylation-stability-and-toxicity-in-vivo
#17
Katerina Papanikolopoulou, Sofia Grammenoudi, Martina Samiotaki, Efthimios M C Skoulakis
Neurodegenerative dementias collectively known as Tauopathies involve aberrant phosphorylation and aggregation of the neuronal protein Tau. The largely neuronal 14-3-3 proteins are also elevated in the Central Nervous System (CNS) and Cerebrospinal Fluid of Tauopathy patients, suggesting functional linkage. We use the simplicity and genetic facility of the Drosophila system to investigate in vivo whether 14-3-3s are causal or synergistic with Tau accumulation in precipitating pathogenesis. Proteomic, biochemical and genetic evidence demonstrate that both Drosophila 14-3-3 proteins interact with human wild type and mutant Tau on multiple sites irrespective of their phosphorylation state...
April 12, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29659823/a-hyperactivating-proinflammatory-ripk2-allele-associated-with-early-onset-osteoarthritis
#18
Michael J Jurynec, Allen D Sawitzke, Timothy C Beals, Michael J Redd, Jeff Stevens, Brith Otterud, Mark H Leppert, David Jonah Grunwald
Osteoarthritis (OA) is a common debilitating disease characterized by abnormal remodeling of the cartilage and bone of the articular joint. Ameliorating therapeutics are lacking due to limited understanding of the molecular pathways affecting disease initiation and progression. Notably, although a link between inflammation and overt OA is well established, the role of inflammation as a driver of disease occurrence is highly disputed. We analyzed a family with dominant inheritance of early-onset OA and found that affected individuals harbored a rare variant allele encoding a significant amino acid change (p...
April 12, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29659804/high-content-screen-for-modifiers-of-niemann-pick-type-c-disease-in-patient-cells
#19
Emily K Pugach, McKenna Feltes, Randal J Kaufman, Daniel S Ory, Anne G Bang
Niemann-Pick type C disease (NPC) is a rare lysosomal storage disease caused primarily by mutations in NPC1. NPC1 encodes the lysosomal cholesterol transport protein NPC1. The most common NPC1 mutation is a missense mutation (NPC1I1061T) that causes misfolding and rapid degradation of mutant protein in the endoplasmic reticulum. Cholesterol accumulates in enlarged lysosomes as a result of decreased levels of lysosomal NPC1I1061T protein in patient cells. There is currently no cure or FDA-approved treatment for patients...
April 12, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29648665/homozygous-taf8-mutation-in-a-patient-with-intellectual-disability-results-in-undetectable-taf8-protein-but-preserved-rna-polymerase-ii-transcription
#20
Farrah El-Saafin, Cynthia Curry, Tao Ye, Jean-Marie Garnier, Isabelle Kolb-Cheynel, Matthieu Stierle, Natalie L Downer, Mathew P Dixon, Luc Negroni, Imre Berger, Tim Thomas, Anne K Voss, William Dobyns, Didier Devys, Laszlo Tora
The human general transcription factor TFIID is composed of the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs). In eukaryotic cells, TFIID is thought to nucleate RNA polymerase II (Pol II) preinitiation complex formation on all protein coding gene promoters and thus, be crucial for Pol II transcription. In a child with intellectual disability, mild microcephaly, corpus callosum agenesis and poor growth we identified a homozygous splice-site mutation in TAF8 (NM_138572.2:c.781-1G>A). Our data indicate that the patient's mutation generates a frame shift and an unstable TAF8 mutant protein with an unrelated C-terminus...
April 10, 2018: Human Molecular Genetics
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