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Intronic Mutation

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https://www.readbyqxmd.com/read/29457796/h3b-8800-an-orally-available-small-molecule-splicing-modulator-induces-lethality-in-spliceosome-mutant-cancers
#1
Michael Seiler, Akihide Yoshimi, Rachel Darman, Betty Chan, Gregg Keaney, Michael Thomas, Anant A Agrawal, Benjamin Caleb, Alfredo Csibi, Eckley Sean, Peter Fekkes, Craig Karr, Virginia Klimek, George Lai, Linda Lee, Pavan Kumar, Stanley Chun-Wei Lee, Xiang Liu, Crystal Mackenzie, Carol Meeske, Yoshiharu Mizui, Eric Padron, Eunice Park, Ermira Pazolli, Shouyong Peng, Sudeep Prajapati, Justin Taylor, Teng Teng, John Wang, Markus Warmuth, Huilan Yao, Lihua Yu, Ping Zhu, Omar Abdel-Wahab, Peter G Smith, Silvia Buonamici
Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor-encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function, but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells...
February 19, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29453960/synaptic-dysfunction-and-altered-excitability-in-c9orf72-als-ftd
#2
Alexander Starr, Rita Sattler
Amyotrophic lateral sclerosis (ALS) is characterized by a progressive degeneration of upper and lower motor neurons, resulting in fatal paralysis due to denervation of the muscle. Due to genetic, pathological and symptomatic overlap, ALS is now considered a spectrum disease together with frontotemporal dementia (FTD), the second most common cause of dementia in individuals under the age of 65. Interestingly, in both diseases, there is a large prevalence of RNA binding proteins (RBPs) that are mutated and considered disease-causing, or whose dysfunction contribute to disease pathogenesis...
February 14, 2018: Brain Research
https://www.readbyqxmd.com/read/29452578/clinical-and-genetic-study-of-20-patients-from-china-with-cornelia-de-lange-syndrome
#3
Mingyan Hei, Xiangyu Gao, Lingqian Wu
BACKGROUND: Cornelia de Lange syndrome (CdLS) is a rare congenital syndrome with no racial difference. The objective of this study is to report the clinical characteristics and genetic study of 20 CdLS cases from China. METHODS: This is an observational study. Suspected patients were referred for further confirmation, clinical treatment, and genetic testing under voluntary condition. Demographic data and family history, data of clinical manifestations including facial dysmorphism and developmental delay of each patient were collected...
February 16, 2018: BMC Pediatrics
https://www.readbyqxmd.com/read/29450726/c9orf72-associated-neurodegeneration-in-als-ftd-breaking-new-ground-in-ribosomal-rna-and-nucleolar-dysfunction
#4
REVIEW
Dustin Herrmann, Rosanna Parlato
Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are neurodegenerative diseases with distinct clinical appearance. However, both share as major genetic risk factor a C9orf72 locus intronic hexanucleotide expansion. The pathogenic pathways associated with the expansion-dependent neuronal toxicity are still poorly understood. Recent efforts to identify common threads of neuronal dysfunction have pointed towards deficits of ribosomal RNA (rRNA) biogenesis and loss of nucleolar integrity, a condition known as nucleolar stress that is an emerging shared feature among neurodegenerative diseases...
February 15, 2018: Cell and Tissue Research
https://www.readbyqxmd.com/read/29450643/variants-in-fix-propeptide-associated-with-vitamin-k-antagonist-hypersensitivity-functional-analysis-and-additional-data-confirming-the-common-founder-mutations
#5
Behnaz Pezeshkpoor, Katrin J Czogalla, Michael Caspers, Ann-Cristin Berkemeier, Kerstin Liphardt, Suvoshree Ghosh, Marco Kellner, Silvia Ulrich, Anna Pavlova, Johannes Oldenburg
One of the most common and unwanted side effects during oral anticoagulant therapy (OAT) is bleeding complications. In rare cases, vitamin K antagonist (VKA)-related bleeding events are associated with mutations affecting the F9 propeptide at amino acid position 37 due to a substitution of alanine to either valine or threonine. Based on our actual cohort of 18 patients, we update the knowledge on this rare phenotype and its origin. A founder mutation for both variants was reconfirmed by haplotype analysis of intronic and extragenic short tandem repeat (STR) polymorphisms with a higher prevalence in Switzerland than in other regions of Europe...
February 15, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29444904/mutation-in-an-alternative-transcript-of-cdkl5-in-a-boy-with-early-onset-seizures
#6
Dale L Bodian, John M Schreiber, Thierry Vilboux, Alina Khromykh, Natalie S Hauser
Infantile-onset epilepsies are a set of severe, heterogeneous disorders for which clinical genetic testing yields causative mutations in ~20-50% of affected individuals. We report the case of a boy presenting with intractable seizures at 2 weeks of age, for whom gene panel testing was unrevealing. Research-based whole genome sequencing of the proband and four unaffected family members identified a de novo mutation, NM_001323289.1:c.2828_2829delGA in CDKL5, a gene associated with X-linked early infantile epileptic encephalopathy 2...
February 14, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29435938/transgene-like-animal-models-using-intronic-micrornas
#7
Shi-Lung Lin, Shin-Ju E Chang, Shao-Yao Ying
Transgenic animal models are valuable tools for testing gene functions and drug mechanisms in vivo. They are also the best similitude for a human body for etiological and pathological research of diseases. All pharmaceutically developed medicines must be proven to be safe and effective in animals before approval by the Food and Drug Administration (FDA) to be used in clinical trials. To this end, the transgenic animal models of diseases serve as the front line of drug evaluation. However, there is currently no transgenic animal model for microRNA (miRNA)-related research...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29435927/gene-silencing-in-vitro-and-in-vivo-using-intronic-micrornas
#8
Shi-Lung Lin, Shao-Yao Ying
MicroRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular messenger RNAs (mRNAs) that contain either complete or partial complementarity, are useful for the design of new therapies against cancer polymorphism and viral mutation. Numerous miRNAs have been reported to induce RNA interference (RNAi), a post-transcriptional gene-silencing mechanism. Recent evidence also indicates that they are involved in the transcriptional regulation of genome activities. They were first discovered in Caenorhabditis elegans as native RNA fragments that modulate a wide range of genetic regulatory pathways during embryonic development, and are now recognized as small gene silencers transcribed from the noncoding regions of a genome...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29434716/%C3%AE-thalassaemia-combined-with-hereditary-spherocytosis-in-the-same-patient
#9
Xiaohong Li, Lin Liao, Xuelian Deng, Jian Huang, Zengfu Deng, Hongying Wei, Wuning Mo, Faquan Lin
A family of four from the Guangxi Zhuang Autonomous Region of China, including a child with α-thalassaemia and hereditary spherocytosis (HS), underwent laboratory identification, and genetic analysis. After harvesting peripheral blood samples from the child patient and his family members, GAP-polymerase chain reaction (PCR) and reverse dot-blot tests were used to identify thalassaemia genotypes. After amplifying exons and the adjacent introns of solute carrier family 4 member 1 (Diego blood group) (SLC4A1), ankyrin 1, spectrin α erythrocytic 1, spectrin β erythrocytic and erythrocyte membrane protein band 4...
February 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29434620/functional-analyses-of-a-novel-splice-variant-in-the-chd7-gene-found-by-next-generation-sequencing-confirm-its-pathogenicity-in-a-spanish-patient-and-diagnose-him-with-charge-syndrome
#10
Olatz Villate, Nekane Ibarluzea, Eugenia Fraile-Bethencourt, Alberto Valenzuela, Eladio A Velasco, Detelina Grozeva, F L Raymond, María P Botella, María-Isabel Tejada
Mutations in CHD7 have been shown to be a major cause of CHARGE syndrome, which presents many symptoms and features common to other syndromes making its diagnosis difficult. Next generation sequencing (NGS) of a panel of intellectual disability related genes was performed in an adult patient without molecular diagnosis. A splice donor variant in CHD7 (c.5665 + 1G > T) was identified. To study its potential pathogenicity, exons and flanking intronic sequences were amplified from patient DNA and cloned into the pSAD® splicing vector...
2018: Frontiers in Genetics
https://www.readbyqxmd.com/read/29425110/a-japanese-patient-with-congenital-central-hypothyroidism-caused-by-a-novel-igsf1-mutation
#11
Takeshi Yamaguchi, Tomoyuki Hothubo, Shuntaro Morikawa, Akie Nakamura, Toshihiko Mori, Toshihiro Tajima
BACKGROUND: IGSF1 abnormality causes diverse symptoms, including congenital central hypothyroidism (CCH), prolactin hyposecretion, testicular enlargement and delayed puberty. CASE PRESENTATION: Here, we report a case of a male patient who visited our hospital with a chief complaint of abdominal pain and short stature, in whom we identified a novel IGSF1 mutation. He was closely examined because of chronic constipation since infancy, persistent abdominal pain at 14 years of age and marked short stature (-4...
February 9, 2018: Journal of Pediatric Endocrinology & Metabolism: JPEM
https://www.readbyqxmd.com/read/29422629/isolating-characterising-and-identifying-a-cry1ac-resistance-mutation-in-field-populations-of-helicoverpa-punctigera
#12
Tom Walsh, Bill James, Maissa Chakroun, Juan Ferré, Sharon Downes
Transgenic cotton expressing insecticidal proteins from Bacillus thuringiensis (Bt) has been grown in Australia for over 20 years and resistance remains the biggest threat. The native moth, Helicoverpa punctigera is a significant pest of cotton. A genotype causing resistance to Cry1Ac in H. punctigera was isolated from the field and a homozygous line established. The phenotype is recessive and homozygous individuals possess 113 fold resistance to Cry1Ac. Individuals that carry Cry1Ac resistance genes are rare in Australia with a frequency of 0...
February 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29422027/ovas-an-open-source-variant-analysis-suite-with-inheritance-modelling
#13
Monika Mozere, Mehmet Tekman, Jameela Kari, Detlef Bockenhauer, Robert Kleta, Horia Stanescu
BACKGROUND: The advent of modern high-throughput genetics continually broadens the gap between the rising volume of sequencing data, and the tools required to process them. The need to pinpoint a small subset of functionally important variants has now shifted towards identifying the critical differences between normal variants and disease-causing ones. The ever-increasing reliance on cloud-based services for sequence analysis and the non-transparent methods they utilize has prompted the need for more in-situ services that can provide a safer and more accessible environment to process patient data, especially in circumstances where continuous internet usage is limited...
February 8, 2018: BMC Bioinformatics
https://www.readbyqxmd.com/read/29419869/-identification-of-a-novel-stk11-gene-mutation-in-a-family-affected-with-hereditary-peutz-jeghers-syndrome
#14
Cuiyang Xu, Yue Ma, Fei Cao, He Zhao, Yongjie Wang, Zewen Xiao, Jiebing Tang, Feihu Yan, Peng Sun, Na Zhang, Ji Tao
OBJECTIVE To explore the genetic basis for a family affected with Peutz-Jeghers syndrome (PJS). METHODS Genomic DNA was extracted from peripheral blood and oral swab samples from the patient and her relatives. Next-generation sequencing (NGS) was used to analyze 106 target genes by capturing the exons and adjacent intronic regions. Suspected pathogenic mutation was verified by NGS. RESULTS A missense STK11 mutation was detected in the proband, which was not reported previously. The mutation has caused substitution of Leucine by Proline...
February 10, 2018: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/29417179/the-dna-double-strand-breakome-of-mouse-spermatids
#15
Marie-Chantal Grégoire, Frédéric Leduc, Martin H Morin, Tiphanie Cavé, Mélina Arguin, Martin Richter, Pierre-Étienne Jacques, Guylain Boissonneault
De novo germline mutations arise preferentially in male owing to fundamental differences between spermatogenesis and oogenesis. Post-meiotic chromatin remodeling in spermatids results in the elimination of most of the nucleosomal supercoiling and is characterized by transient DNA fragmentation. Using three alternative methods, DNA from sorted populations of mouse spermatids was used to confirm that double-strand breaks (DSB) are created in elongating spermatids and repaired at later steps. Specific capture of DSB was used for whole-genome mapping of DSB hotspots (breakome) for each population of differentiating spermatids...
February 7, 2018: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29413232/pah-mutation-spectrum-and-correlation-with-pku-manifestation-in-north-jiangsu-province-population
#16
Zhen-Wen Wang, Shi-Wen Jiang, Bao-Cheng Zhou
Phenylketonuria (PKU) is a common autosomal recessive disorder of phenylalanine metabolism and mainly results a deficiency of phenylalanine hydroxylase gene (PAH). The incidence of various PAH mutations have race and ethnicity differences. We report a spectrum of PAH mutations complied from 35 PKU children who are all Chinese Han population from north Jiangsu in this study. All 13 exons and their flanking intron sequences of PAH were determined by Ion Torrent PGM™ sequencing. The relationship of genotype and phenotype was analyzed based on the sum of the arbitrary value (AV) values of the two alleles...
February 2018: Kaohsiung Journal of Medical Sciences
https://www.readbyqxmd.com/read/29408779/pathogenic-significance-of-scn1a-splicing-variants-causing-dravet-syndrome-improving-diagnosis-with-targeted-sequencing-for-variants-by-in-silico-analysis
#17
Nejat Mahdieh, Sepideh Mikaeeli, Reza Shervin Badv, Azadeh Gharehzadeh Shirazi, Majid Maleki, Bahareh Rabbani
OBJECTIVES: Genetic heterogeneity of epileptic encephalopathy (IEE) mandates the use of gene-panels for diagnosis. PATIENTS AND METHODS: A 36-gene-panel next-generation sequencing was applied for IEE in two Iranian families. A literature search was performed using keywords to identify reported splicing mutations in SCN1A and perform genotype-phenotype correlation. RESULTS: An update of splicing mutations revealed 147 variants with 65.75% of them de novo mutations...
January 31, 2018: Clinical Neurology and Neurosurgery
https://www.readbyqxmd.com/read/29405992/characterization-of-novel-large-duplications-in-the-msh2-gene-of-three-unrelated-lynch-syndrome-patients
#18
Raffaella Liccardo, Marina De Rosa, Giovanni Battista Rossi, Gabriele Rigler, Paola Izzo, Francesca Duraturo
Lynch syndrome (LS) is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1, MSH2, MSH6, and PMS2. Most of genetic variants in the MMR genes predisposing to LS are point mutations, small deletions and insertions but large genomic rearrangements in the MMR genes also predisposing to Lynch syndrome. In this study, we report a novel, large rearrangement of the MSH2 gene, manifested by a duplication spanning a 14,846-bps region from intron 7 through intron 9. The breakpoints of this rearrangement were characterized by sequencing...
February 2018: Cancer Genetics
https://www.readbyqxmd.com/read/29403086/association-of-cdkal1-nucleotide-variants-with-the-risk-of-non-syndromic-cleft-lip-with-or-without-cleft-palate
#19
Agnieszka Gaczkowska, Kacper Żukowski, Barbara Biedziak, Kamil K Hozyasz, Piotr Wójcicki, Małgorzata Zadurska, Margareta Budner, Agnieszka Lasota, Anna Szponar-Żurowska, Paweł P Jagodziński, Adrianna Mostowska
Although the aetiology of non-syndromic cleft lip with or without cleft palate (nsCL/P) has been studied extensively, knowledge regarding the role of genetic factors in the pathogenesis of this common craniofacial anomaly is still limited. We conducted a follow-up association study to confirm that CDKAL1 nucleotide variants identified in our genome-wide association study (GWAS) for nsCL/P are associated with the risk of this anomaly. In addition, we performed a sequence analysis of the selected CDKAL1 exons...
February 5, 2018: Journal of Human Genetics
https://www.readbyqxmd.com/read/29400714/haploinsufficiency-leads-to-neurodegeneration-in-c9orf72-als-ftd-human-induced-motor-neurons
#20
Yingxiao Shi, Shaoyu Lin, Kim A Staats, Yichen Li, Wen-Hsuan Chang, Shu-Ting Hung, Eric Hendricks, Gabriel R Linares, Yaoming Wang, Esther Y Son, Xinmei Wen, Kassandra Kisler, Brent Wilkinson, Louise Menendez, Tohru Sugawara, Phillip Woolwine, Mickey Huang, Michael J Cowan, Brandon Ge, Nicole Koutsodendris, Kaitlin P Sandor, Jacob Komberg, Vamshidhar R Vangoor, Ketharini Senthilkumar, Valerie Hennes, Carina Seah, Amy R Nelson, Tze-Yuan Cheng, Shih-Jong J Lee, Paul R August, Jason A Chen, Nicholas Wisniewski, Victor Hanson-Smith, T Grant Belgard, Alice Zhang, Marcelo Coba, Chris Grunseich, Michael E Ward, Leonard H van den Berg, R Jeroen Pasterkamp, Davide Trotti, Berislav V Zlokovic, Justin K Ichida
An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion...
February 5, 2018: Nature Medicine
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