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Intronic Mutation

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https://www.readbyqxmd.com/read/29239282/generation-of-human-induced-pluripotent-stem-cells-from-wolfram-syndrome-type-2-patients-bearing-the-c-103-1g-a-cisd2-mutation-for-disease-modeling
#1
Alberto La Spada, Aikaterini Ntai, Stefano Genovese, Maurizio Rondinelli, Pasquale De Blasio, Ida Biunno
Wolfram syndrome (WFS) is a rare autosomal premature aging syndrome that shows signs of diabetes mellitus (DM), optic atrophy (OA) and deafness in addition to central nervous system and endocrine complications. The frequent form of WFS, type 1 (WFS1), harbours causative mutations in the WFS1 gene, while the rare form or type 2 (WFS2), involves CISD2. Mutations in these two genes are recognized by a subset of variable clinical symptoms and a set of overlapping features. Here we report on the generation of stable human induced pluripotent stem cells (hiPSCs) derived from primary fibroblasts of a previously reported Italian family with CISD2 mutation (c...
December 14, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/29237418/a-donor-splice-site-mutation-in-cisd2-generates-multiple-truncated-non-functional-isoforms-in-wolfram-syndrome-type-2-patients
#2
Monica Cattaneo, Lucia La Sala, Maurizio Rondinelli, Edoardo Errichiello, Orsetta Zuffardi, Annibale Alessandro Puca, Stefano Genovese, Antonio Ceriello
BACKGROUND: Mutations in the gene that encodes CDGSH iron sulfur domain 2 (CISD2) are causative of Wolfram syndrome type 2 (WFS2), a rare autosomal recessive neurodegenerative disorder mainly characterized by diabetes mellitus, optic atrophy, peptic ulcer bleeding and defective platelet aggregation. Four mutations in the CISD2 gene have been reported. Among these mutations, the homozygous c.103 + 1G > A substitution was identified in the donor splice site of intron 1 in two Italian sisters and was predicted to cause a exon 1 to be skipped...
December 13, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/29236234/assessment-of-the-functional-impact-of-germline-brca1-2-variants-located-in-non-coding-regions-in-families-with-breast-and-or-ovarian-cancer-predisposition
#3
E Santana Dos Santos, S M Caputo, L Castera, M Gendrot, A Briaux, M Breault, S Krieger, P K Rogan, E J Mucaki, L J Burke, I Bièche, C Houdayer, D Vaur, D Stoppa-Lyonnet, M A Brown, F Lallemand, E Rouleau
PURPOSE: The molecular mechanism of breast and/or ovarian cancer susceptibility remains unclear in the majority of patients. While germline mutations in the regulatory non-coding regions of BRCA1 and BRCA2 genes have been described, screening has generally been limited to coding regions. The aim of this study was to evaluate the contribution of BRCA1/2 non-coding variants. METHODS: Four BRCA1/2 non-coding regions were screened using high-resolution melting analysis/Sanger sequencing or next-generation sequencing on DNA extracted from index cases with breast and ovarian cancer predisposition (3926 for BRCA1 and 3910 for BRCA2)...
December 13, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29230583/mutation-screening-of-chinese-treacher-collins-syndrome-patients-identified-novel-tcof1-mutations
#4
Ying Chen, Luo Guo, Chen-Long Li, Jing Shan, Hai-Song Xu, Jie-Ying Li, Shan Sun, Shao-Juan Hao, Lei Jin, Gang Chai, Tian-Yu Zhang
Treacher Collins syndrome (TCS) (OMIM 154500) is a rare congenital craniofacial disorder with an autosomal dominant manner of inheritance in most cases. To date, three pathogenic genes (TCOF1, POLR1D and POLR1C) have been identified. In this study, we conducted mutational analysis on Chinese TCS patients to reveal a mutational spectrum of known causative genes and show phenotype-genotype data to provide more information for gene counselling and future studies on the pathogenesis of TCS. Twenty-two TCS patients were recruited from two tertiary referral centres, and Sanger sequencing for the coding exons and exon-intron boundaries of TCOF1, POLR1D and POLR1C was performed...
December 11, 2017: Molecular Genetics and Genomics: MGG
https://www.readbyqxmd.com/read/29229990/tumor-suppressor-p53-links-ceramide-metabolism-to-dna-damage-response-through-alkaline-ceramidase-2
#5
Ruijuan Xu, Monica Garcia-Barros, Sally Wen, Fang Li, Chih-Li Lin, Yusuf A Hannun, Lina M Obeid, Cungui Mao
p53 mediates the DNA damage response (DDR) by regulating the expression of genes implicated in cell cycle arrest, senescence, programmed cell death (PCD), and metabolism. Herein we demonstrate that human alkaline ceramidase 2 (ACER2) is a novel transcriptional target of p53 and that its transactivation by p53 mediates the DDR. We found that p53 overexpression or its activation by ionizing radiation (IR) upregulated ACER2 in cells. Two putative p53 responsive elements (p53REs) were found in its first intron of the ACER2 gene, and Chromatin Immunoprecipitation (ChIP) assays in combination with promoter activity assays demonstrated that these p53REs are the bona fide p53 binding sites that mediate ACER2 transactivation by p53...
December 11, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29228280/new-intronic-fibroblast-growth-factor-receptor-1-fgfr1-mutation-leading-to-disrupted-splicing-and-kallmann-syndrome
#6
J Känsäkoski, K Vaaralahti, T Raivio
Congenital hypogonadotropic hypogonadism (CHH), which can present with a defective sense of smell (Kallmann syndrome, KS), is a clinically and genetically heterogeneous disorder. Over 31 genes have been associated with CHH, but most of the patients still lack a molecular genetic diagnosis. Some cases may be explained by mutations that disrupt the splicing of already established CHH genes but that are unrecognized either because they are located deep in introns or are not predicted to disrupt splicing. Here we identified a patient with a previously unreported Fibroblast Growth Factor Receptor 1 (FGFR1) mutation, c...
December 8, 2017: Human Reproduction
https://www.readbyqxmd.com/read/29228267/the-effects-of-sex-biased-gene-expression-and-x-linkage-on-rates-of-sequence-evolution-in-drosophila
#7
José Luis Campos, Keira Johnston, Brian Charlesworth
A faster rate of adaptive evolution of X-linked genes compared with autosomal genes (the faster-X effect) can be caused by the fixation of recessive or partially recessive advantageous mutations. This effect should be largest for advantageous mutations that affect only male fitness, and least for mutations that affect only female fitness. We tested these predictions in Drosophila melanogaster by using coding and functionally significant non-coding sequences of genes with different levels of sex-biased expression...
December 8, 2017: Molecular Biology and Evolution
https://www.readbyqxmd.com/read/29227985/low-frequency-of-fabry-disease-in-patients-with-common-heart-disease
#8
Raphael Schiffmann, Caren Swift, Nathan McNeill, Elfrida R Benjamin, Jeffrey P Castelli, Jay Barth, Lawrence Sweetman, Xuan Wang, Xiaoyang Wu
PurposeTo test the hypothesis that undiagnosed patients with Fabry disease exist among patients affected by common heart disease.MethodsGlobotriaosylceramide in random whole urine using tandem mass spectroscopy, α-galactosidase A activity in dried blood spots, and next-generation sequencing of pooled or individual genomic DNA samples supplemented by Sanger sequencing.ResultsWe tested 2,256 consecutive patients: 852 women (median age 65 years (19-95)) and 1,404 men (median age 65 years (21-92)). The primary diagnoses were coronary artery disease (n = 994), arrhythmia (n = 607), cardiomyopathy (n = 138), and valvular disease (n = 568)...
October 26, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29214630/a-del-phenotype-attributed-to-rhd-exon-9-sequence-deletion-slipped-strand-mispairing-and-blood-group-polymorphisms
#9
Genghis H Lopez, Robyn M Turner, Eunike C McGowan, Elizna M Schoeman, Stacy A Scott, Helen O'Brien, Glenda M Millard, Eileen V Roulis, Amanda J Allen, Yew-Wah Liew, Robert L Flower, Catherine A Hyland
BACKGROUND: The RhD blood group antigen is extremely polymorphic and the DEL phenotype represents one such class of polymorphisms. The DEL phenotype prevalent in East Asian populations arises from a synonymous substitution defined as RHD*1227A. However, initially, based on genomic and cDNA studies, the genetic basis for a DEL phenotype in Taiwan was attributed to a deletion of RHD Exon 9 that was never verified at the genomic level by any other independent group. Here we investigate the genetic basis for a Caucasian donor with a DEL partial D phenotype and compare the genomic findings to those initial molecular studies...
December 6, 2017: Transfusion
https://www.readbyqxmd.com/read/29206898/somatic-mutation-footprinting-reveals-a-unique-tetra-nucleotide-signature-associated-with-intron-exon-boundaries-in-lung-cancer
#10
Samuel Wormald, Anita Lerch, Dmitri Mouradov, Liam O'Connor
Cigarette smoke comprises a large number of carcinogenic substances that can increase DNA mutation load in epithelial cells of the mouth, throat and lungs. While a strong C:A substitution preference is abundant in tobacco-related cancer genomes, detection of complex or less abundant somatic mutation signatures may be confounded by the heterogeneity of carcinogens present in smoke. Tri-nucleotide signatures are defined for a variety of somatic mutation processes, yet the extent to which this configuration optimally defines and discriminates between mutational processes is not clear...
December 1, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29202719/an-in-vitro-splicing-assay-reveals-the-pathogenicity-of-a-novel-intronic-variant-in-atp6v0a4-for-autosomal-recessive-distal-renal-tubular-acidosis
#11
Tomohiko Yamamura, Kandai Nozu, Yuya Miyoshi, Keita Nakanishi, Junya Fujimura, Tomoko Horinouchi, Shogo Minamikawa, Nobuo Mori, Rika Fujimaru, Koichi Nakanishi, Takeshi Ninchoji, Hiroshi Kaito, Taniguchi-Ikeda Mariko, Ichiro Morioka, Masafumi Matsuo, Kazumoto Iijima
BACKGROUND: Autosomal recessive distal renal tubular acidosis (dRTA) is a rare hereditary disease caused by pathogenic variants in the ATP6V0A4 gene or ATP6V1B1 gene, and characterized by hyperchloremic metabolic acidosis with normal anion gap, hypokalemia, hypercalciuria, hypocitraturia and nephrocalcinosis. Although several intronic nucleotide variants in these genes have been detected, all of them fell in the apparent splice consensus sequence. In general, transcriptional analysis is necessary to determine the effect on function of the novel intronic variants located out of splicing consensus sequences...
December 4, 2017: BMC Nephrology
https://www.readbyqxmd.com/read/29201125/glutaric-aciduriatype-1-clinical-and-molecular-study-in-iranian-patients-3-novel-mutations
#12
Zahra Pirzadeh, Massoud Houshmand, Jafar Nasiri, Mohsen Mollamohammadi, Mostafa Sedighi, Seyed Hassan Tonekaboni
Objective: Glutaricaciduria type 1 (GA1), is a rare, treatable neuro metabolic disease, due to glutaryl- CoA dehydrogenase (GCDH) gene mutation.In regions without neonatal blood screening (NBS), patients are diagnosed in symptomatic period. This study was carried out to assess patients with GA1 for clinical, biochemical, neuroimaging findings and GCDH gene mutations analysis. Materials & Methods: In this cross-sectional study, clinical manifestation, neuroimaging and metabolic findings of eleven Iranian GA1 patients of MofidChildren's Hospital, Tehran, Iranbetween 2001 and 2011,were evaluated...
2017: Iranian Journal of Child Neurology
https://www.readbyqxmd.com/read/29193502/foxp3-mutations-causing-early-onset-insulin-requiring-diabetes-but-without-other-features-of-immune-dysregulation-polyendocrinopathy-enteropathy-x-linked-syndrome
#13
Jessica L Hwang, Soo-Young Park, Honggang Ye, May Sanyoura, Ashley N Pastore, David Carmody, Daniela Del Gaudio, Janna F Wilson, Craig L Hanis, Xiaoming Liu, Gil Atzmon, Benjamin Glaser, Louis H Philipson, Siri Atma W Greeley
Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause "immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked" (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3...
November 29, 2017: Pediatric Diabetes
https://www.readbyqxmd.com/read/29188620/-analysis-of-genotype-and-phenotype-of-sec23b-gene-in-a-family-affected-with-congenital-dyserythropoietic-anemia-type-ii
#14
Dongliang Li, Bolun Li, Shanshan Qu, Wei Cao, Yaping Yang, Yintu Ma, Tianwen Hou
OBJECTIVE: To detect potential mutation in a family affected with congenital dyserythropoietic anemia type II (CDA II). METHODS: Targeted sequence capture and next-generation sequencing (NGS) were used to analyze the exons and exon-intron boundaries of the SEC23B gene in a clinically suspected CDA II patient. Genotypes of the relatives were validated by Sanger sequencing. Potential impact of amino acid substitution on the structure and function of SEC23B protein was predicted with MutationTaster and PolyPhen-2...
December 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/29188506/design-and-in-vitro-use-of-antisense-oligonucleotides-to-correct-pre-mrna-splicing-defects-in-inherited-retinal-dystrophies
#15
Alejandro Garanto, Rob W J Collin
Antisense oligonucleotides (AONs) are small molecules able to bind to the pre-mRNA and modulate splicing. The increasing amount of intronic mutations leading to pseudoexon insertion in genes underlying inherited retinal dystrophies (IRDs) has highlighted the potential of AONs as a therapeutic tool for these disorders. Here we describe how to design and test AON molecules in vitro in order to correct pre-mRNA splicing defects involved in IRDs.
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29187863/smooth-an-hnrnp-l-homolog-might-decrease-mitochondrial-metabolism-by-post-transcriptional-regulation-of-isocitrate-dehydrogenase-idh-and-other-metabolic-genes-in-the-sub-acute-phase-of-traumatic-brain-injury
#16
Arko Sen, Katherine Gurdziel, Jenney Liu, Wen Qu, Oluwademi O Nuga, Rayanne B Burl, Maik Hüttemann, Roger Pique-Regi, Douglas M Ruden
Traumatic brain injury (TBI) can cause persistent pathological alteration of neurons. This may lead to cognitive dysfunction, depression and increased susceptibility to life threatening diseases, such as epilepsy and Alzheimer's disease. To investigate the underlying genetic and molecular basis of TBI, we subjected w1118Drosophila melanogaster to mild closed head trauma and found that mitochondrial activity is reduced in the brains of these flies 24 h after inflicting trauma. To determine the transcriptomic changes after mild TBI, we collected fly heads 24 h after inflicting trauma, and performed RNA-seq analyses...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/29187847/a-multilayered-control-of-the-human-survival-motor-neuron-gene-expression-by-alu-elements
#17
REVIEW
Eric W Ottesen, Joonbae Seo, Natalia N Singh, Ravindra N Singh
Humans carry two nearly identical copies of Survival Motor Neuron gene: SMN1 and SMN2. Mutations or deletions of SMN1, which codes for SMN, cause spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Aberrant expression or localization of SMN has been also implicated in other pathological conditions, including male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. SMN2 fails to compensate for the loss of SMN1 due to skipping of exon 7, leading to the production of SMNΔ7, an unstable protein...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29186127/mismatch-repair-prefers-exons
#18
Dashiell J Massey, Amnon Koren
A new analysis of cancer genomes identifies a decrease in the mutation burden of exons, but not introns, as compared to expectation. This difference can be explained by preferential recruitment of the DNA mismatch repair machinery to a protein modification that marks exons.
November 29, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29184640/investigation-of-five-common-mutations-on-phenylalanine-hydroxylase-gene-of-phenylketonuria-patients-from-two-provinces-in-north-of-iran
#19
Daniel Zamanfar, Hossein Jalali, Mohammad Reza Mahdavi, Morteza Maadanisani, Hossein Zaeri, Eynollah Asadpoor
Background: There are more than 500 different mutations on phenylalanine hydroxylase (PAH) gene that is responsible for phenylketonuria (PKU) diseases and the spectrum of these mutations is varied in different populations. The main clinical manifestation of untreated patients is severe mental retardation. The PAH gene, that is 90 kb long, is consisted of 13 exons and 12 introns. The aim of the present study was to identify the frequency of five common mutations on PAH gene among patients with PKU in Mazandaran and Golestan provinces including c...
2017: International Journal of Preventive Medicine
https://www.readbyqxmd.com/read/29184627/medical-sequencing-of-de-novo-ectodermal-dysplasia-in-identical-twins-and-evaluation-of-the-potential-eligibility-for-recombinant-eda-therapy
#20
Adriana Modesto, Catherine Ventura, Kathleen Deeley, Deborah Studen-Pavlovich, Alexandre R Vieira
The purpose of this study was to test two 8-year-old identical twins with ectodermal dysplasia (ED) and their unaffected parents for the presence of mutations in the EDA gene with the hypothesis that they might be carrying a de novo mutation in EDA and potentially eligible for recombinant EDA therapy. DNA was extracted using saliva samples obtained from the identical twin girls and both parents. PCR products of Ectodyplasin A (EDA), Ectodysplasin Receptor (EDAR), Ectodysplasin Receptor Associated Death Domain (EDARADD), and Connexin-30 (GJB6) were sequenced by the Sanger method and the results analyzed using a reference sequence...
2017: Journal of Dental Research, Dental Clinics, Dental Prospects
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