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https://www.readbyqxmd.com/read/28550350/recent-advances-in-the-study-of-immunodeficiency-and-dna-damage-response
#1
REVIEW
Tomohiro Morio
DNA breaks can be induced by exogenous stimuli or by endogenous stress, but are also generated during recombination of V, D, and J genes (V(D)J recombination), immunoglobulin class switch recombination (CSR). Among various DNA breaks generated, DNA double strand break (DSB) is the most deleterious one. DNA damage response (DDR) is initiated when DSBs are detected, leading to DNA break repair by non-homologous end joining (NHEJ). The process is critically important for the generation of diversity for foreign antigens; and failure to exert DNA repair leads to immunodeficiency such as severe combined immunodeficiency and hyper-IgM syndrome...
May 26, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28550267/amyloid-precursor-protein-haploinsufficiency-preferentially-mediates-brain-iron-accumulation-in-mice-transgenic-for-the-huntington-s-disease-mutation
#2
Kiersten Berggren, Sonal Agrawal, Julia A Fox, Justin Hildenbrand, Ryan Nelson, Ashley I Bush, Jonathan H Fox
BACKGROUND: Huntington's disease (HD) is an autosomal dominant disorder caused by a CAG expansion in the huntingtin gene that results in expression of mutant huntingtin protein. Iron accumulates in HD brain neurons. Amyloid precursor protein (APP) promotes neuronal iron export. However, the role of APP in brain iron accumulation in HD is unclear. OBJECTIVE: To determine the effects of APP insufficiency on HD in YAC128 mice. METHODS: We crossed APP hemizygous mice (APP+/-) with YAC128 mice that are transgenic (Tg) for human mutant huntingtin (hmHTT) to generate APP+/+ hmHTT-/-, APP+/- hmHTT-/-, APP+/+ hmHTT+/- and APP+/- hmHTT+/- progeny...
May 24, 2017: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/28550247/two-novel-mutations-in-the-first-transmembrane-domain-of-presenilin1-cause-young-onset-alzheimer-s-disease
#3
Collin Y Liu, Yu Ohki, Taisuke Tomita, Satoko Osawa, Bruce R Reed, William Jagust, Victoria Van Berlo, Lee-Way Jin, Helena C Chui, Giovanni Coppola, John M Ringman
BACKGROUND: The presenilin-1 protein (PS1) is the catalytic unit of γ-secretase implicated in the production of abnormally long forms of amyloid-β (Aβ), including Aβ42, proteins thought critical in the pathogenesis of Alzheimer's disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the PSEN1 gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis. OBJECTIVE: To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of PSEN1 as well as biochemical features in one and neuropathological findings in the other...
May 25, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28550183/somatic-mutation-spectrum-in-monoclonal-gammopathy-of-undetermined-significance-indicates-a-less-complex-genomic-landscape-compared-to-multiple-myeloma
#4
Aneta Mikulasova, Christopher P Wardell, Alexander Murison, Eileen M Boyle, Graham H Jackson, Jan Smetana, Zuzana Kufova, Ludek Pour, Viera Sandecka, Martina Almasi, Pavla Vsianska, Evzen Gregora, Petr Kuglik, Roman Hajek, Faith E Davies, Gareth J Morgan, Brian A Walker
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant precursor of multiple myeloma with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as IGH translocations, RB1 deletion, 1q gain, hyperdiploidy or RAS genes mutations, little is known about the molecular mechanism of malignant transformation. We have performed whole exome sequencing together with CGH+SNP array analysis in 33 flow-cytometry separated abnormal plasma cell samples from MGUS patients to describe somatic gene mutations and chromosome changes at the genome-wide level...
May 26, 2017: Haematologica
https://www.readbyqxmd.com/read/28550180/a-novel-de-novo-mutation-in-prkag2-gene-infantile-onset-phenotype-and-signaling-pathway-involved
#5
Yanchun Xu, Alex Gray, David Grahame Hardie, Alper Uzun, Sunil Shaw, James F Padbury, Chanika Phornphutkul, Yi-Tang Tseng
PRKAG2 encodes the γ2-subunit isoform of the 5' AMP-activated protein kinase (AMPK), a heterotrimeric enzyme with major roles in regulation of energy metabolism in response to cellular stress. Mutations in PRKAG2 have been implicated in a unique hypertrophic cardiomyopathy (HCM) characterized by cardiac glycogen overload, ventricular preexcitation and hypertrophy. We identified a novel, de novo PRKAG2 mutation (K475E) in a neonate with prenatal onset of HCM. We aimed to investigate the cellular impact, signaling pathways involved and therapeutic options for K475E mutation using cells stably expressing human wild type (WT) or the K475E mutant...
May 26, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28550176/mechanical-behavior-and-matrisome-gene-expression-in-aneurysm-prone-thoracic-aorta-of-newborn-lysyl-oxidase-knockout-mice
#6
Marius Catalin Staiculescu, Jungsil Kim, Robert P Mecham, Jessica Wagenseil
Mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysm and dissection (TAAD). Mice that do not express Lox (Lox(-/-)) die soon after birth and have 60% and 40% reductions in elastin- and collagen-specific crosslinks, respectively. LOX inactivation could also change the expression of secreted factors, structural matrix, and matrix-associated proteins that constitute the aortic matrisome. We hypothesize that the absence of Lox will change the mechanical behavior of the aortic wall due to reduced elastin and collagen crosslinking and alter the expression levels of matrisome and smooth muscle cell (SMC) genes in a vascular location-specific manner...
May 26, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28550065/exceptional-durable-response-to-everolimus-in-a-patient-with-biphenotypic-breast-cancer-harboring-an-stk11-variant
#7
Christine A Parachoniak, Andrew Rankin, Bernadette Gaffney, Ryan Hartmaier, Dan Spritz, Rachel L Erlich, Vincent A Miller, Deborah Morosini, Phil Stephens, Jeffrey S Ross, John Keech, Juliann Chmielecki
Metastatic triple negative breast cancer comprises 12-17% of breast cancers and carries a poor prognosis relative to other breast cancer subtypes. Treatment options in this disease are largely limited to systemic chemotherapy. A majority of clinical studies assessing efficacy of targeted therapeutics (e.g. the mTOR inhibitor everolimus) in advanced breast cancer patients have not utilized predictive genomic biomarker-based selection and have reported only modest improvement in clinical outcome relative to standard of care...
May 26, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28550064/transient-silencing-of-dna-repair-genes-improves-targeted-gene-integration-in-the-filamentous-fungus-trichoderma-reesei
#8
Pak Yang Chum, Georg Schmidt, Markku Saloheimo, Christopher P Landowski
Trichoderma reesei is a filamentous fungus that is used world-wide to produce industrial enzymes. Industrial strains have traditionally been created though systematic strain improvement by mutagenesis and screening approaches. It is also desirable to specifically manipulate genes of the organism to further improve and modify the strain. Targeted integration in filamentous fungi is typically hampered by very low frequencies of homologous recombination. To address this limitation we have developed a simple transient method for silencing genes in T...
May 26, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28550060/surface-sensing-for-flagellar-gene-expression-on-solid-media-in-paenibacillus-sp-naist15-1
#9
Kazuo Kobayashi, Yu Kanesaki, Hirofumi Yoshikawa
A rhizosphere Gram-positive bacterial isolate, Paenibacillus sp. NAIST15-1, exhibits intriguing motility behavior on hard agar media. Paenibacillus sp. shows increased transcription of flagellar genes and hyperflagellation when transferred from liquid to solid media. Hyperflagellated cells form wandering colonies that are capable of moving around on the surface of media containing ≥1.5% agar. Transposon mutagenesis was used to identify genes critical for motility. In addition to flagellar genes, this mutagenesis identified five non-flagellar structural genes that were important for motility...
May 26, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28550040/kras-g12d-expression-in-lung-resident-myeloid-cells-promotes-pulmonary-lch-like-neoplasm-sensitive-to-statin-treatment
#10
Tamihiro Kamata, Susan Giblett, Catrin Pritchard
Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm associated with somatic mutations in the genes involved in the RAF/MEK/ERK signaling pathway. Recently, oncogenic mutations in NRAS/KRAS, upstream regulators of the RAF/MEK/ERK pathway, have been reported in pulmonary, but not in non-pulmonary, LCH cases, suggesting organ-specific contribution of oncogenic RAS to LCH pathogenesis. Using a mouse model expressing KRAS(G12D) in the lung by nasal delivery of adenoviral Cre, here we show that KRAS(G12D) expression in lung-resident myeloid cells induces pulmonary LCH-like neoplasms comprised of pathogenic CD11c(high)F4/80+CD207+ cells...
May 26, 2017: Blood
https://www.readbyqxmd.com/read/28550027/exceptional-response-to-nivolumab-and-stereotactic-body-radiation-therapy-sbrt-in-neuroendocrine-cervical-carcinoma-with-high-tumor-mutational-burden-management-considerations-from-the-center-for-personalized-cancer-therapy-at-uc-san-diego-moores-cancer-center
#11
Andrew Sharabi, Sangwoo Shawn Kim, Shumei Kato, Philip D Sanders, Sandip Pravin Patel, Parag Sanghvi, Elizabeth Weihe, Razelle Kurzrock
Neuroendocrine carcinoma of the cervix is an ultra-rare malignancy with a poor prognosis and limited treatment options. Checkpoint blockade immunotherapy has rapidly developed into an emerging standard of care for several common disease types. Interestingly, in preclinical and retrospective clinical data, radiation therapy has been demonstrated to synergize with checkpoint inhibitors. Here we report a patient with metastatic, chemotherapy-refractory neuroendocrine carcinoma who presented with partial bowel obstruction due to a large tumor burden...
May 26, 2017: Oncologist
https://www.readbyqxmd.com/read/28550025/mineralocorticoid-receptor-null-mice-informing-cell-type-specific-roles
#12
Timothy James Cole, Morag Young
The mineralocorticoid receptor (MR) mediates the actions of two important adrenal corticosteroid hormones, aldosterone and cortisol. The cell signalling roles of the MR in vivo have expanded enormously since the cloning of human MR gene 30 years ago and the first MR gene knockout in mice nearly 20 years ago. Complete ablation of the MR revealed important roles postnatally for regulation of kidney epithelial functions, with MR-null mice dying 1-2 weeks postnatally from renal salt wasting and hyperkalaemia, with elevated plasma renin and aldosterone...
May 26, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28550017/a-lysine-desert-protects-a-novel-domain-in-the-slx5-slx8-sumo-targeted-ub-ligase-to-maintain-sumoylation-levels-in-saccharomyces-cerevisiae
#13
Pragati Sharma, Janet R Mullen, Minxing Li, Mikel Zaratiegui, Samuel F Bunting, Steven J Brill
Protein modification by the small ubiquitin-like modifier (SUMO) plays important roles in genome maintenance. In Saccharomyces cerevisiae, proper regulation of sumoylation is known to be essential for viability in certain DNA repair mutants. Here we find the opposite result; proper regulation of sumoylation is lethal in certain DNA repair mutants. Yeast cells lacking the repair factors TDP1 and WSS1 are synthetically lethal due to their redundant roles in removing Top1-DNA covalent complexes (Top1ccs). A screen for suppressors of tdp1∆ wss1∆ synthetic lethality isolated mutations in genes known to control global sumoylation levels including ULP1, ULP2, SIZ2 and SLX5 The results suggest that alternative pathways of repair become available when sumoylation levels are altered...
May 26, 2017: Genetics
https://www.readbyqxmd.com/read/28550013/an-essential-regulatory-system-originating-from-polygenic-transcriptional-rewiring-of-phop-phoq-of-xanthomonas-campestris
#14
Bao-Yu Peng, Yue Pan, Ru-Jiao Li, Jin-Wei Wei, Fang Liang, Li Wang, Fang-Fang Wang, Wei Qian
How essential, regulatory genes originate and evolve is intriguing because mutations of these genes not only lead to lethality in organisms, but also have pleiotropic effects since they control the expression of multiple downstream genes. Therefore, the evolution of essential, regulatory genes is not only determined by genetic variations of their own sequences, but also by the biological function of downstream genes and molecular mechanisms of regulation. To understand the origin of essential, regulatory genes, experimental dissection of the complete regulatory cascade is needed...
May 26, 2017: Genetics
https://www.readbyqxmd.com/read/28550012/the-genetic-architecture-of-ovariole-number-in-drosophila-melanogaster-genes-with-major-quantitative-and-pleiotropic-effects
#15
Amanda S Lobell, Rachel R Kaspari, Yazmin L Serrano Negron, Susan T Harbison
Ovariole number has a direct role in the number of eggs produced by an insect, suggesting that it is a key morphological fitness trait. Many studies have documented the variability of ovariole number and its relationship to other fitness and life-history traits in natural populations of Drosophila However, the genes contributing to this variability are largely unknown. Here we conducted a genome-wide association study of ovariole number in a natural population of flies. Using mutations and RNAi-mediated knockdown, we confirmed the effects of twenty-four candidate genes on ovariole number, including a novel gene, anneboleyn (formerly CG32000), that impacts both ovariole morphology and numbers of offspring produced...
May 26, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28549927/molecular-classification-of-adult-diffuse-gliomas-conflicting-idh1-idh2-atrx-and-1p-19q-results
#16
Leomar Y Ballester, Jason T Huse, Guilin Tang, Gregory N Fuller
Until recently, the diagnosis of brain tumors was primarily based on microscopic examination of hematoxylin and eosin (H&E) stained tissue sections. The updated World Health Organization (WHO) classification of tumours of the central nervous system (CNS) incorporates genetic alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. Hence, under the new classification system the diagnosis of diffuse gliomas incorporates the evaluation of mutations in the IDH1 and IDH2 genes and simultaneous deletion of chromosomes 1p and 19...
May 23, 2017: Human Pathology
https://www.readbyqxmd.com/read/28549772/codon-optimized-rpgr-improves-stability-and-efficacy-of-aav8-gene-therapy-in-two-mouse-models-of-x-linked-retinitis-pigmentosa
#17
M Dominik Fischer, Michelle E McClements, Cristina Martinez-Fernandez de la Camara, Julia-Sophia Bellingrath, Daniyar Dauletbekov, Simon C Ramsden, Doron G Hickey, Alun R Barnard, Robert E MacLaren
X-linked retinitis pigmentosa (XLRP) is generally a severe form of retinitis pigmentosa, a neurodegenerative, blinding disorder of the retina. 70% of XLRP cases are due to mutations in the retina-specific isoform of the gene encoding retinitis pigmentosa GTPase regulator (RPGR(ORF15)). Despite successful RPGR(ORF15) gene replacement with adeno-associated viral (AAV) vectors being established in a number of animal models of XLRP, progression to human trials has not yet been possible. The inherent sequence instability in the purine-rich region of RPGR(ORF15) (which contains highly repetitive nucleotide sequences) leads to unpredictable recombination errors during viral vector cloning...
May 24, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28549597/prolactin-receptor-targeting-in-breast-and-prostate-cancers-new-insights-into-an-old-challenge
#18
REVIEW
Vincent Goffin
In the era of precision medicine, the identification of new targets is a constant challenge to improve cancer therapy. Preclinical investigations, epidemiological studies and analyses of tissue specimens from patients strongly support the contribution of prolactin receptor (PRLR) signaling to breast and prostate tumorigenesis and cancer progression. Although a clear causative link with mutations of the genes encoding prolactin or its receptor is lacking, increased PRLR signaling in these cancers can be assessed by the overexpression of cognate proteins and is often confirmed by over-activation of downstream signaling effectors...
May 23, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28549500/greater-preclinical-atherosclerosis-in-treated-monogenic-familial-hypercholesterolemia-vs-polygenic-hypercholesterolemia
#19
Mahtab Sharifi, Elizabeth Higginson, Sven Bos, Angela Gallivan, Darren Harvey, Ka Wah Li, Amali Abeysekera, Angela Haddon, Helen Ashby, Kate E Shipman, Jackie A Cooper, Marta Futema, Jeanine E Roeters van Lennep, Eric J G Sijbrands, Mourad Labib, Devaki Nair, Steve E Humphries
BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia...
May 13, 2017: Atherosclerosis
https://www.readbyqxmd.com/read/28549490/whole-genome-analysis-reveals-new-insights-into-macrolide-resistance-in-mycoplasma-pneumoniae
#20
Shao Li Li, Hong Mei Sun, Bao Li Zhu, Fei Liu, Han Qing Zhao
OBJECTIVE: Mutations in 23S rRNA gene are known to be associated with macrolide resistance in Mycoplasma pneumoniae (M. pneumoniae). However, these mutations alone do not fully explain the high resistance rates in Asia. The aim of this study was to investigate other possible mutations involved in macrolide resistance in M. pneumoniae. METHODS: The whole genomes of 10 clinical isolates of M. pneumoniae with macrolide resistance were sequenced by Illumina HiSeq2000 platform...
May 2017: Biomedical and Environmental Sciences: BES
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