36 results on '"Splice Donor Site"'
Search Results
2. Splice‐site variant in the RPS7 5′‐UTR leads to a decrease in the mRNA level and development of Diamond‐Blackfan anemia.
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Skorodumova, Liubov O., Davydenko, Ksenia A., Filatova, Alexandra Y., Skoblov, Mikhail Yu, Kulemin, Nikolay A., Khadzhieva, Maryam B., Zakharova, Elena S., Gordeeva, Veronika D., Smetanina, Nataliya S., Fedyushkina, Irina V., Anastasevich, Lyudmila A., and Larin, Sergey S.
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PURE red cell aplasia , *GENE expression , *DNA copy number variations , *ANEMIA , *RIBOSOMAL proteins - Abstract
Diamond‐Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by erythroid aplasia. Pathogenic variants in ribosomal protein (RP) genes, GATA1, TSR2, and EPO, are considered to be the etiology of DBA. Variants in 5′‐untranslated regions (UTRs) of these genes are poorly studied and can complicate the variant interpretation. We investigated the functional consequences NM_001011.4:c.‐19 + 1G > T variant in the donor splice‐site of the RPS7 5′‐UTR. This variant was found in a family where two sons with DBA were carriers. Father, who also had this variant, developed myelodysplastic syndrome, which caused his death. Search for candidate causal variants and copy number variations in DBA‐associated genes left RPS7 variant as the best candidate. Trio whole exome sequencing analysis revealed no pathogenic variants in other genes. Functional analysis using luciferase expression system revealed that this variant leads to disruption of splicing. Also, a decrease in the levels of mRNA and protein expression was detected. In conclusion, the established consequences of 5′‐UTR splice‐site variant c.‐19 + 1G > T in the RPS7 gene provide evidence that it is likely pathogenic. [ABSTRACT FROM AUTHOR]
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- 2023
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3. A founder RDH5 splice site mutation leads to retinitis punctata albescens in two inbred Pakistani kindreds.
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Khan, Rizwan, Shabbir, Rana Muhammad Kamran, Raza, Irum, Abdullah, Umair, Naeem, Muhammad Asif, Ahmed, Ashfaque, Malik, Sajid, Hu, Zhengmao, and Xia, Kun
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RETINAL degeneration , *NONSENSE mutation , *HOMOZYGOSITY , *EXONS (Genetics) , *MISSENSE mutation , *PATIENT-family relations - Abstract
Background: Retinitis punctate albescens (RPA) is a rare form of retinal dystrophy characterized by congenital stationary night blindness and a characteristic fundus appearance. Missense or nonsense mutations in RDH5 in homozygous or heterozygous state have been implicated in RPA. Material and methods: Two consanguineous Pakistani kindreds with the highly variable manifestation of RPA were studied. Whole-exome sequencing was applied to the index subjects in both families. Sanger sequencing of the candidate RDH5 variant was carried out. Pathogenicity of the detected variant was assessed through bioinformatics tools. Results: The ophthalmic examination through full-field electroretinogram of affected patients in both families was consistent with RPA. A novel splice donor variant at the first exon/intron boundary of RDH5 (NM_002905.3: c.-33 + 2dup) segregated in recessive fashion with the clinical phenotype in both families. One of the heterozygous variant carriers was also observed to have a milder expression of retinal flecks. Haplotype analysis surrounding the splice variant and pattern of runs of homozygosity were suggestive of common ancestry in these families. Conclusion: This is the first report of any pathogenic splice variant at first exon/intron boundary implicated in RPA and suggests another mechanism through which RDH5 variants could be associated with eye phenotype. This study also highlights the importance of a thorough phenotypic evaluation of heterozygous mutation carriers who may exhibit milder symptoms. [ABSTRACT FROM AUTHOR]
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- 2020
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4. Determination of Pathogenicity of Breast Cancer 1 Gene Variants using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Guidelines.
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Brown, Angela, Zamanpoor, Mansour, Love, Donald R., and Prosser, Debra O.
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MEDICAL genetics , *MOLECULAR pathology , *BRCA genes , *MEDICAL genomics , *MOLECULAR association - Abstract
Molecular diagnostic laboratories screen for mutations in disease-causing genes in order to confirm a clinical diagnosis. The classification of DNA variants as ‘pathogenic’ or ‘likely pathogenic’ mutations creates a workflow bottleneck, which becomes increasingly challenging as greater number of genes are screened. The classification challenge is also acute if there are conflicting reports regarding pathogenicity and differing classification criteria between laboratories. This study aimed to compare two procedures for the classification of variants in the breast cancer (BRCA)1 gene. Methods: This bioinformatic study was conducted at LabPLUS, Auckland, New Zealand, from February to June 2017. DNA was extracted from peripheral blood samples of 30 patients and gene library construction was carried out using a commercially available targeted panel for the BRCA1 and BRCA2 genes. The genes were subsequently sequenced and the sequence data analysed. The guidelines published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/ AMP) provides a comprehensive framework for the interpretation of variants in genes that are associated with Mendelian disorders. The use of these guidelines were compared to the variant classifications that were achieved by reference to those reported in the BRCA Exchange database. Results: The results showed concordance between the two classification protocols for a panel of 30 BRCA1 gene variants, although the transparency in following the ACMG/AMP guidelines provides a diagnostic laboratory with a generalisable approach that allows laboratorydirected revisions to be undertaken in light of new information. Conclusion: The ACMG/AMP-based guidelines were applied to a cohort of patients with BRCA1 gene variants. The use of these guidelines provides a system which creates consistency in variant interpretation and supports subsequent clinical management. [ABSTRACT FROM AUTHOR]
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- 2019
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5. An Alert to Possible False Positives With a Commercial Assay for MET Exon 14 Skipping
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Takashi Teishikata, Yasushi Yatabe, Yuki Shinno, Takako Ishiyama, Jumpei Kashima, Yoshihisa Kobayashi, Taisuke Mori, Tatsuya Yoshida, and Kouya Shiraishi
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Capmatinib ,business.industry ,Exons ,Proto-Oncogene Proteins c-met ,Clinical trial ,Exon ,Splice Donor Site ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Mutation ,False positive paradox ,Humans ,Medicine ,In patient ,business - Abstract
Introduction Because molecular-targeted drugs against MET exon 14 (METex14) skipping have been approved, molecular testing of the alteration has added to clinical guidelines. There are several such assays, but methodological issues have been reported. Methods METex14 skipping results from three assays (Oncomine DxTT, ArcherMET, and laboratory-developed reverse-transcriptase polymerase chain reaction test [LDT RT-PCR]) were compared in a relatively small series of the specimens diagnosed as advanced NSCLC (n = 50). Results The ArcherMET and LDT RT-PCR results were identical for all 50 samples, but eight samples had discordant results between Oncomine DxTT and the other two assays. All eight samples had METex14 skipping with Oncomine DxTT and wild-type signals with ArcherMET and LDT RT-PCR. The discordance might be caused by the homopolymeric error of the splice donor site with Oncomine DxTT, and false positives could be distinguished by relatively low read counts. Conclusions Although the caution in detecting METex14 skipping focuses on false negatives in the literature, false positives were first noted at a relatively high frequency (8 of 26, 30.8%) in this study. According to the results of previous clinical trials using the other tyrosine kinase inhibitors, it could be surmised that MET inhibitor treatment in patients without METex14 skipping is detrimental. Clinicians need to be alert to the false positives that can lead to harmful treatments.
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- 2021
6. Dihydropyrimidine Dehydrogenase (DPD) Deficiency: Novel Mutations in the DPD Gene
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Van Kuilenburg, Andre B. P., Haasjes, Janet, Meinsma, Rutger, Waterham, Hans R., Vrelem, Peter, Van Gennip, Alebrt H., Back, Nathan, editor, Cohen, Irun R., editor, Kritchevsky, David, editor, Lajtha, Abel, editor, Paoletti, Rodolfo, editor, Zoref-Shani, Esther, editor, and Sperling, Oded, editor
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- 2002
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7. The suppression of metallothionein synthesis inhibits the growth of leukemia P388 cells
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Takeda, Atsushi, Hisada, Harumi, Okada, Shoji, Mata, John E., Iversen, Patrick L., Ebadi, Manuchair, and Klaassen, Curtis D., editor
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- 1999
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8. The Genetic Basis of APRT Deficiency
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Sahota, A., Chen, J., Stambrook, P. J., Tischfield, J. A., and Gresser, Ursula, editor
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- 1993
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9. Expression and Regulation of the Maize Spm Transposable Element
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Fedoroff, N. V., Masson, P., Banks, J. A., Herrmann, R. G., editor, and Larkins, B. A., editor
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- 1991
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10. Poor Splice-Site Recognition in a Humanized Zebrafish Knockin Model for the Recurrent Deep-Intronic c.7595-2144A > G Mutation in USH2A
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Ralph Slijkerman, Theo A. Peters, Milou Gerits, Sanne Broekman, Erik de Vrieze, Erwin van Wijk, Hannie Kremer, Lisette Hetterschijt, and Alexander Goloborodko
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0301 basic medicine ,Retinal degeneration ,RNA Splicing ,Usher syndrome ,Biology ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,03 medical and health sciences ,0302 clinical medicine ,Splice Donor Site ,All institutes and research themes of the Radboud University Medical Center ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,CRISPR ,Zebrafish ,Genetics ,Extracellular Matrix Proteins ,Intron ,medicine.disease ,biology.organism_classification ,Introns ,030104 developmental biology ,Gene Expression Regulation ,Larva ,Mutation ,RNA splicing ,Mutation (genetic algorithm) ,Animal Science and Zoology ,RNA Splice Sites ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
The frequent deep-intronic c.7595-2144AG mutation in intron 40 of USH2A generates a high-quality splice donor site, resulting in the incorporation of a pseudoexon (PE40) into the mature transcript that is predicted to prematurely terminate usherin translation. Aberrant USH2A pre-mRNA splicing could be corrected in patient-derived fibroblasts using antisense oligonucleotides. With the aim to study the effect of the c.7595-2144AG mutation and USH2A splice redirection on retinal function, a humanized zebrafish knockin model was generated, in which 670 basepairs of ush2a intron 40 were exchanged for 557 basepairs of the corresponding human sequence using an optimized CRISPR/Cas9-based protocol. However, in the retina of adult homozygous humanized zebrafish, only 7.4% ± 3.9% of ush2a transcripts contained the human PE40 sequence and immunohistochemical analyses revealed no differences in the usherin expression and localization between the retina of humanized and wild-type zebrafish larvae. Nevertheless, we were able to partially correct aberrant ush2a splicing using a PE40-targeting antisense morpholino. Our results indicate a clear difference in splice-site recognition by the human and zebrafish splicing machinery. Therefore, we propose a protocol in which the effect of human splice-modulating mutations is studied in a zebrafish-specific cell-based splice assay before the generation of a humanized zebrafish knockin model.
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- 2018
11. Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency.
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Soneda, Akiko, Adachi, Masanori, Muroya, Koji, Asakura, Yumi, Takagi, Masaki, Hasegawa, Tomonobu, Inoue, Hiroshi, and Itakura, Mitsuo
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Abstract: Objective: To elucidate the pathogenesis of isolated growth hormone (GH) deficiency in a Japanese girl without consanguinity. Design: A 2-year-old girl of height 77.2cm (−3.0 SD for Japanese girls) was found to have an insulin-like growth factor (IGF)-1 level of 7ng/mL and IGF binding protein-3 (IGFBP-3) level of 0.41μg/mL. GH responded modestly to a series of pharmacological stimulants, increasing to 2.81ng/mL with insulin-induced hypoglycemia, 3.78ng/mL with arginine, and 3.93 with GH-releasing hormone (GHRH). Following direct sequencing of the GHRH receptor (GHRHR) gene, evaluation by the luciferase reporter assay, immunofluorescence study, and in vitro splicing assay with minigene constructs was conducted. Results: Novel compound heterozygous GHRHR gene mutations were identified in the patient. A p.G136V substitution elicited no luciferase activity increment in response to GHRH stimulation, with normal membranous expression. Splicing assay demonstrated that the IVS2+3a>g mutation would lead to aberrant splicing. Conclusions: A case of isolated GH deficiency due to novel GHRHR gene mutations was identified. [Copyright &y& Elsevier]
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- 2013
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12. Aberrant splicing events caused by insertion of genes of interest into expression vectors.
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Cheng Y, Kang XZ, Chan P, Ye ZW, Chan CP, and Jin DY
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- Alternative Splicing genetics, Animals, Cells, Cultured, Exons genetics, Humans, Mice, Mutation, RNA Splice Sites, RNA Splicing genetics
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Background: Expression of genes of interest from plasmids or lentiviral vectors is one of the most common tools in molecular and gene therapy. Aberrant splicing between the inserted gene of interest and downstream vector sequence has not been systematically analyzed. Methods: Formation of aberrant fusion transcripts and proteins was detected by RT-PCR, sequencing, Western blotting and mass spectrometry. Bioinformatic analysis was performed to identify all human and mouse genes prone to vector-dependent aberrant splicing. Selected genes were experimentally validated. Results: When we expressed human FACI in cultured cells, an aberrant splicing event was found to occur between FACI transcript and downstream plasmid sequence through one exon-exon junction in FACI that accidentally contributes a splice donor site. To explore whether this could be a general phenomenon, we searched the whole human and mouse genomes for protein-coding genes that harbor an exon-exon junction resembling a splice donor site. Almost all genes prone to this type of aberrant splicing were identified. A total of 17 genes among the hits were randomly selected for experimental validation. RT-PCR and sequencing results verified that 13 genes were aberrantly spliced on the identified exon-exon junctions. In addition, all 17 genes were aberrantly spliced on their V5 tag sequence. Aberrant fusion protein expression from all 17 genes was validated by immunoblotting. Aberrant splicing was prevented by recoding the V5 tag or the splice sites. Conclusions: Our study revealed an unexpectedly high frequency of vector-dependent aberrant splicing events. Aberrant formation of the resulting fusion proteins could undermine the accuracy of gain-of-function studies and might cause potential side effects when the therapeutic gene is expressed in vivo . Our work has implications in improving vector construction and epitope tagging for gene expression and therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)
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- 2022
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13. An α-Thalassemia Phenotype in a Dutch Hindustani, Caused by a New Point Mutation that Creates an Alternative Splice Donor Site in the First Exon of the α2-Globin Gene.
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Harteveld, Cornelis L., Wijermans, Pierre W., van Delft, Peter, Rasp, Ellen, Haak, Hans L., and Giordano, Piero C.
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THALASSEMIA , *HEMOGLOBINOPATHY , *HEMOLYTIC anemia , *MESSENGER RNA , *BLOOD diseases , *CARRIER proteins - Abstract
The proband is an elderly woman (79 years of age) of Surinamese–Hindustani origin, suspected of being a carrier of a nondeletional α-thalassemia (thal) because of a moderate microcytic hypochromic anemia at normal ferritin levels and in the absence of any other α-thal deletions. Sequence analysis revealed a silent mutation (GGC→GGT) at codon 22 of the α2-globin gene. This mutation generates a splice donor site consensus sequence (GGTGAG) between codons 22 and 23. The abnormally spliced mRNA leads to a premature termination between codons 48 and 49. The presence of a downstream intron may induce the intracellular degradation of the affected mRNA, a pathway known as nonsense mediated decay (NMD), and this explains the α+-thal phenotype observed in the patient. The codon 22 (GGC→GGT) transition described in this report is the first mutation creating a splice donor site in one of the α-globin genes. [ABSTRACT FROM AUTHOR]
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- 2004
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14. Efficient replication of full-length murine leukemia viruses modified at the dimer initiation site regions
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Aagaard, Lars, Rasmussen, Søren Vestergaard, Mikkelsen, Jacob Giehm, and Pedersen, Finn Skou
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RETROVIRUSES , *GENOMES , *DIMERS - Abstract
Retroviruses encapsidate two copies of full-length viral RNA molecules linked together as a dimeric genome. RNA stem loop structures harboring palindromic (or “kissing”) loop sequences constitute important cis-elements for viral dimerization known as dimer initiation sites (DIS). In murine leukemia virus (MLV), a 10-mer and a 16-mer palindrome (DIS-1 and DIS-2, respectively) located in the viral leader region mediate dimerization in vitro and affect dimer stability of vector RNA in vivo. We have investigated the effect on viral replication of introducing deletions or nucleotide substitutions within these palindromes in a full-length MLV genome. Our results demonstrate that viruses modified at the dimer initiation site regions are viable and show wild-type levels of RNA encapsidation. One mutant lacking the DIS-1 palindrome was severely impaired and displayed an increased cellular ratio of spliced versus genomic RNA that most likely contributes to the inefficient replication. The implications for development of DIS-modified retrovirus-based vectors are discussed. [Copyright &y& Elsevier]
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- 2004
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15. Full in-frame exon 3 skipping of BRCA2 confers high risk of breast and/or ovarian cancer
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Marine Guillaud-Bataille, Pascaline Gaidrat, Ana Vega, Dominique Stoppa-Lyonnet, Inge Søkilde, Mads Thomassen, Ana Peixoto, Florence Coulet, Claude Houdayer, Nancy Uhrhammer, Danièle Muller, Ambre Petitalot, Sandrine M. Caputo, Rita D. Brandão, Hélène Tubeuf, Laurent Castera, Virginie Moncoutier, Olga M. Sinilnikova, Aura Carreira, Alexandra Martins, Gaia Castelain, Francesca Damiola, Åsa Ehlén, Etienne Rouleau, Capucine Delnatte, Nadia Boutry-Kryza, Mélanie Léoné, Myriam Bronner, Manuel R. Teixeira, Sophie Demontety, Henriette Roed Nielsen, Amanda B. Spurdle, Uffe Birk Jensen, Sophie Krieger, Cédrick Lefol, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, Institut Curie [Paris], Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Stress génotoxiques et cancer, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Paris-Sud - Paris 11 (UP11), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Genetics, Portuguese Oncology Institute, Genomic Medicine Group, University of Santiago de Compostela, Université Paris Descartes - Paris 5 (UPD5), Centre René Gauducheau, CRLCC René Gauducheau, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Odense University Hospital, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique, Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Groupement Hospitalier Est, Equipe 6, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Division of Genetics and Population Health, Queensland Institute of Medical Research, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Universidade de Santiago de Compostela [Spain] (USC ), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and COLO, Mouniati
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0301 basic medicine ,PALB2 ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Germline ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Breast cancer ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,medicine ,skin and connective tissue diseases ,Gene ,splice donor site ,Genetics ,variants ,Variants ,Cancer ,medicine.disease ,BRCA2 Protein ,3. Good health ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,RNA splicing defects ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Splice donor site ,Ovarian cancer ,BRCA2 exon3 ,Research Paper - Abstract
International audience; Germline pathogenic variants in the BRCA2 gene are associated with a cumulative high risk of breast/ovarian cancer. Several BRCA2 variants result in complete loss of the exon-3 at the transcript level. The pathogenicity of these variants and the functional impact of loss of exon 3 have yet to be established. As a collaboration of the COVAR clinical trial group (France), and the ENIGMA consortium for investigating breast cancer gene variants, this study evaluated 8 BRCA2 variants resulting in complete deletion of exon 3. Clinical information for 39 families was gathered from Portugal, France, Denmark and Sweden. Multifactorial likelihood analyses were conducted using information from 293 patients, for 7 out of the 8 variants (including 6 intronic). For all variants combined the likelihood ratio in favor of causality was 4.39*1025. These results provide convincing evidence for the pathogenicity of all examined variants that lead to a total exon 3 skipping, and suggest that other variants that result in complete loss of exon 3 at the molecular level could be associated with a high risk of cancer comparable to that associated with classical pathogenic variants in BRCA1 or BRCA2 gene. In addition, our functional study shows, for the first time, that deletion of exon 3 impairs the ability of cells to survive upon Mitomycin-C treatment, supporting lack of function for the altered BRCA2 protein in these cells. Finally, this study demonstrates that any variant leading to expression of only BRCA2 delta-exon 3 will be associated with an increased risk of breast and ovarian cancer.
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- 2018
16. Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects
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Ingrid M.E. Frohn-Mulder, Yvonne M. Hoedemaekers, Michelle Michels, Michiel Dalinghaus, Johanna C. Herkert, Irenaeus F.M. de Coo, Arthur van den Wijngaard, Dennis Dooijes, Ronald R. de Krijger, Marja W. Wessels, MUMC+: DA KG Lab Centraal Lab (9), RS: CARIM - R2 - Cardiac function and failure, Genetica & Celbiologie, Klinische Genetica, Clinical Genetics, Pediatrics, Cell biology, Pathology, Cardiology, and Neurology
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Heart Defects, Congenital ,Male ,Heterozygote ,Pathology ,medicine.medical_specialty ,DNA Mutational Analysis ,Cardiomyopathy ,SPLICE DONOR SITE ,Case Reports ,Gene mutation ,Biology ,Compound heterozygosity ,medicine.disease_cause ,PHENOTYPE ,Sudden death ,Article ,FAMILIAL HYPERTROPHIC CARDIOMYOPATHY ,Electrocardiography ,Fatal Outcome ,SUDDEN-DEATH ,Cardiomyopathy, Hypertrophic, Familial ,medicine ,Genetics ,Journal Article ,Humans ,Genetic Predisposition to Disease ,Genetics(clinical) ,Genetics (clinical) ,Mutation ,Heart septal defect ,Heart Septal Defects ,Homozygote ,Infant, Newborn ,Infant ,LEFT-VENTRICULAR NONCOMPACTION ,ADULTS ,medicine.disease ,PREVALENCE ,Echocardiography ,Failure to thrive ,BINDING-PROTEIN-C ,Left ventricular noncompaction ,Female ,SARCOMERE MUTATIONS ,medicine.symptom ,Carrier Proteins ,GENE-MUTATIONS - Abstract
Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous or homozygous pathogenic MYBPC3 mutations and describe their clinical characteristics. All four children presented with feeding difficulties, failure to thrive, and dyspnea. They died from cardiac failure before age 13 weeks. Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded. All of them had septal defects. Two patients were compound heterozygotes for the pathogenic c.2373dup p.(Trp792fs) and c.2827C > T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C > T mutations. All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n=21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life. In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy. In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients.
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- 2015
17. Mutations which Stabilize myc Transcripts and Enhance myc Transcription in Two Mouse Plasmacytomas
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Bauer, S. R., Piechaczyk, M., Marcu, K. B., Nordan, R. P., Potter, M., Mushinski, J. F., Clarke, A., editor, Compans, R. W., editor, Cooper, M., editor, Eisen, H., editor, Goebel, W., editor, Koprowski, H., editor, Melchers, F., editor, Oldstone, M., editor, Vogt, P. K., editor, Wagner, H., editor, Wilson, I., editor, Melchers, Fritz, editor, and Potter, Michael, editor
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- 1986
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18. First Detection of a Splice Acceptor Site β-Thalassemia Mutation: IVS-I-130 (HBB: c.93-1G C) in a Chinese Patient
- Author
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Yanqing Tang, Qiang Zhang, Sheng He, Yuan Wei, Chenguang Zheng, Qiuli Chen, and Shaoke Chen
- Subjects
Male ,China ,Genotype ,Thalassemia ,Clinical Biochemistry ,DNA Mutational Analysis ,beta-Globins ,Biology ,Young Adult ,Splice Donor Site ,Asian People ,medicine ,Humans ,splice ,Genetics (clinical) ,Genetics ,Biochemistry (medical) ,beta-Thalassemia ,Hematology ,medicine.disease ,Molecular biology ,Phenotype ,Acceptor ,Introns ,Mutation (genetic algorithm) ,Mutation ,RNA Splice Sites - Abstract
We present the first description of a Chinese patient with a rare β-thalassemia (β-thal) mutation IVS-I-130 (HBB: c.93-1G > C). This mutation is a splice donor site mutation, and is associated with a β0-thal phenotype.
- Published
- 2015
19. A ‘Nonsense’ Mutation Leads to Aberrant Splicing of hMLH1 in a German Hereditary Non-polyposis Colorectal Cancer Family
- Author
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Baehring, J., Sutter, C., Kadmon, M., Doeberitz, M. V. Knebel, and Gebert, J.
- Published
- 2006
- Full Text
- View/download PDF
20. Molecular defects in the α-N-acetylglucosaminidase gene in Italian Sanfilippo type B patients
- Author
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Tessitore, Alessandra, Villani, Guglielmo R. D., Di Domenico, Carmela, Filocamo, Mirella, Gatti, Rosanna, and Di Natale, Paola
- Published
- 2000
- Full Text
- View/download PDF
21. Cryptic splice site activation by a splice donor site mutation of dystrophin intron 64 is determined by intronic splicing regulatory elements
- Author
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Hisahide Nishio, Van Khanh Tran, Tomoko Lee, Yasuhiro Takeshima, Masaaki Matsumoto, A. Nishuda, Hiroyuki Awano, D. Vu, Emma Tabe Eko Niba, and Masafumi Matsuo
- Subjects
Genetics ,Splice site mutation ,Intron ,Biology ,Cryptic splice site ,Splice Donor Site ,Neurology ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,RNA splicing ,biology.protein ,Neurology (clinical) ,Dystrophin ,Genetics (clinical) - Published
- 2016
22. A Distinct mRNA Encoding a Soluble Form of ICAM-1 Molecule Expressed in Human Tissues
- Author
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Toru Wakatsuki, Minoru Ishizawa, Michihiro Ohtsubo, Mikio Yamamoto, Nariyoshi Shinomiya, Fumihiro Kimura, and Kotohiko Kimura
- Subjects
Molecular Sequence Data ,Biology ,Frameshift mutation ,Splice Donor Site ,Humans ,Molecule ,Amino Acid Sequence ,RNA, Messenger ,Cloning, Molecular ,Cells, Cultured ,Sequence Deletion ,ICAM-1 ,Messenger RNA ,Base Sequence ,Frameshifting, Ribosomal ,Sequence Analysis, DNA ,General Medicine ,Intercellular Adhesion Molecule-1 ,Molecular biology ,Transmembrane protein ,Alternative Splicing ,Gene Expression Regulation ,Solubility ,Organ Specificity ,Cytoplasm ,Cytokines ,Primer (molecular biology) - Abstract
A soluble form of ICAM-1 (sICAM-1) have been observed in normal human serum (Rothlein et al., J. Immunol. 147, 3788-3793) and at elevated levels in inflammatory and tumor bearing status (Seth et al., Lancet, 338, 83-84; Giavazzi et al., Canc. Res. 52, 2628-2630; Harning et al., Canc. Res., 51, 5003-5005). However, the mechanism to produce the sICAM-1 has been still unknown. In this report we presented evidence for the presence of the mRNA specifically encoding sICAM-1, which is probably generated by alternative splice donor site selection. A 19-base deletion occurred right upstream of the transmembrane region gave rise to reading frameshift and eliminate the entire transmembrane and cytoplasmic domains, resulting in incapability of ICAM-1 molecules to reside in the membrane. A reverse transcription-polymerase chain reaction (RT-PCR) using a primer pair specific to sICAM-1 revealed a positive expression in all tissues analyzed, though the amount and the ratio to the conventional species varied slightly from tissue to tissue. Inflammatory cytokines displayed a complex pattern in the ICAM-1 mRNA expression depending on the combination of cytokines and the cultured cell lines used.
- Published
- 1995
23. Autosomal dominant malignant and catecholamine-producing paraganglioma caused by a splice donor site mutation in SDHC
- Author
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Peter Lohse, Dieter Engelhardt, Stephan Niemann, and Ulrich Müller
- Subjects
Adult ,Biology ,Carotid Body Tumor ,Exon ,Catecholamines ,Splice Donor Site ,Paraganglioma ,Genetics ,medicine ,Humans ,Transversion ,Genetics (clinical) ,Genes, Dominant ,Intron ,Membrane Proteins ,Exons ,medicine.disease ,Magnetic Resonance Imaging ,Molecular biology ,Introns ,Human genetics ,Succinate Dehydrogenase ,Mutation ,Mutation (genetic algorithm) ,Catecholamine ,Female ,RNA Splice Sites ,medicine.drug - Abstract
Mutations in SDHC cause autosomal dominant paraganglioma, type 3 (PGL3), and have to date been demonstrated in only one family. Here, we report on a novel mutation in a patient with a malignant, catecholamine-producing paraganglioma at the carotid bifurcation. The mutation is a G--T transversion at position +1 of intron 5 of the SDHC gene, leading to the deletion of exon 5 and a shift in the reading frame.
- Published
- 2003
24. A novel splice site mutation in the EDAR gene underlies autosomal recessive hypohidrotic ectodermal dysplasia in a Pakistani family
- Author
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Wasim Ahmad, Ghazanfar Ali, Muhammad Jawad Hassan, Naveed Wasif, and Muhammad Tariq
- Subjects
Male ,Pathology ,medicine.medical_specialty ,animal structures ,Sequence analysis ,Genes, Recessive ,Dermatology ,medicine.disease_cause ,Exon ,Splice Donor Site ,stomatognathic system ,medicine ,Humans ,Point Mutation ,Pakistan ,Hypohidrotic ectodermal dysplasia ,Gene ,Genetics ,Family Health ,Mutation ,Splice site mutation ,integumentary system ,Base Sequence ,business.industry ,Edar Receptor ,Homozygote ,Exons ,medicine.disease ,Pedigree ,Phenotype ,Haplotypes ,Ectodermal Dysplasia, Hypohidrotic, Autosomal Recessive ,embryonic structures ,Pediatrics, Perinatology and Child Health ,Female ,RNA Splice Sites ,business ,Congenital disorder - Abstract
Hypohidrotic ectodermal dysplasia is a rare congenital disorder that results in abnormalities in the structures of ectodermal origin: hair, teeth, and eccrine sweat glands. DNA sequence analysis of EDAR gene in a Pakistani family, demonstrating autosomal recessive form of hypohidrotic ectodermal dysplasia, identified a novel homozygous mutation affecting splice donor site of exon 5 [IVS5+1G > or = C] of the gene.
- Published
- 2010
25. Full in-frame exon 3 skipping of BRCA2 confers high risk of breast and/or ovarian cancer.
- Author
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Caputo SM, Léone M, Damiola F, Ehlen A, Carreira A, Gaidrat P, Martins A, Brandão RD, Peixoto A, Vega A, Houdayer C, Delnatte C, Bronner M, Muller D, Castera L, Guillaud-Bataille M, Søkilde I, Uhrhammer N, Demontety S, Tubeuf H, Castelain G, Jensen UB, Petitalot A, Krieger S, Lefol C, Moncoutier V, Boutry-Kryza N, Nielsen HR, Sinilnikova O, Stoppa-Lyonnet D, Spurdle AB, Teixeira MR, Coulet F, Thomassen M, and Rouleau E
- Abstract
Germline pathogenic variants in the BRCA2 gene are associated with a cumulative high risk of breast/ovarian cancer. Several BRCA2 variants result in complete loss of the exon-3 at the transcript level. The pathogenicity of these variants and the functional impact of loss of exon 3 have yet to be established. As a collaboration of the COVAR clinical trial group (France), and the ENIGMA consortium for investigating breast cancer gene variants, this study evaluated 8 BRCA2 variants resulting in complete deletion of exon 3. Clinical information for 39 families was gathered from Portugal, France, Denmark and Sweden. Multifactorial likelihood analyses were conducted using information from 293 patients, for 7 out of the 8 variants (including 6 intronic). For all variants combined the likelihood ratio in favor of causality was 4.39*10
25 . These results provide convincing evidence for the pathogenicity of all examined variants that lead to a total exon 3 skipping, and suggest that other variants that result in complete loss of exon 3 at the molecular level could be associated with a high risk of cancer comparable to that associated with classical pathogenic variants in BRCA1 or BRCA2 gene. In addition, our functional study shows, for the first time, that deletion of exon 3 impairs the ability of cells to survive upon Mitomycin-C treatment, supporting lack of function for the altered BRCA2 protein in these cells. Finally, this study demonstrates that any variant leading to expression of only BRCA2 delta-exon 3 will be associated with an increased risk of breast and ovarian cancer., Competing Interests: CONFLICTS OF INTEREST All the other authors declare to have no conflicts of interest.- Published
- 2018
- Full Text
- View/download PDF
26. Two point mutations (313 + 1G→A and 313 + 1G→T) in the splice donor site of intron 3 of the low-density lipoprotein receptor gene are associated with familial hypercholesterolemia
- Author
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Ole Faergeman, Niels Gregersen, Peter Steen Hansen, Henrik Jensen, and L. G. Jensen
- Subjects
Genetics ,Splice Donor Site ,Point mutation ,Intron ,medicine ,Familial hypercholesterolemia ,Biology ,Low Density Lipoprotein Receptor Gene ,medicine.disease ,Genetics (clinical) - Published
- 1996
27. Comparative genetic analysis: the utility of mouse genetic systems for studying human monogenic disease
- Author
-
Oliver, Peter L., Bitoun, Emmanuelle, and Davies, Kay E.
- Published
- 2007
- Full Text
- View/download PDF
28. Alpha-thalassemia genes in Israel: deletional and nondeletional mutations in patients of various origins
- Author
-
Lea Shalmon, Rina Zaizov, and Chava Kirschmann
- Subjects
Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,Mutation ,social sciences ,Alpha-thalassemia ,Gene deletion ,Biology ,medicine.disease ,medicine.disease_cause ,Globins ,Hemoglobinopathy ,Splice Donor Site ,alpha-Thalassemia ,medicine ,Humans ,In patient ,Globin ,Israel ,Gene ,geographic locations ,Genetics (clinical) ,Gene Deletion - Abstract
The alpha-thalassemia mutations in 34 Jewish patients of various origins and in 13 Arab patients have been identified using DNA technologies. Middle Eastern Jews and Arabs have both deletional and nondeletional mutations, but in the former the most frequent mutation is the Mediterranean deletion while in Arabs it is the polyadenylation signal mutation. Another nondeletional mutation, the 5 bp deletion at the IVS1 splice donor site has only been found in Arabs. Yemenite and European Jews have only deletional mutations and the most frequent is the 3.7 kb deletion. A long deletion that involves the two alpha-globin genes, is found only in Yemenis.
- Published
- 1996
29. Targeting branch sites of new exons?
- Author
-
Igor Vorechovsky
- Subjects
Genetics ,Exon ,Spliceosome ,Splice Donor Site ,Splice site mutation ,Mutation (genetic algorithm) ,Alu element ,splice ,Biology ,Exome ,Genetics (clinical) - Abstract
Martinez et al 1 reported an interesting case of Dubowitz-like syndrome associated with an acceptor splice site mutation, leading to the use of a cryptic splice donor site in an Alu sequence. Their explanation for the resulting aberrant transcripts was limited to a referral to Alu polyA tails and Alu -derived microRNAs.1 Upon mutation of acceptor sites, the spliceosome machinery tries to find suitable alternative 3′ splice sites nearby. If none is available, which …
- Published
- 2012
30. Exon skipping associated with A--G transition at +4 of the IVS33 splice donor site of the neurofibromatosis type 1 (NF1) gene
- Author
-
Stylianos E. Antonarakis, Michael A. Morris, Pierre Hutter, and Célla D. Delozier-Blanchet
- Subjects
DNA, Complementary ,Neurofibromatosis 1 ,RNA Splicing ,Molecular Sequence Data ,Biology ,medicine.disease_cause ,Polymerase Chain Reaction ,Neurofibromatosis 1/genetics ,Splice Donor Site ,Genes, Neurofibromatosis 1 ,Genetics ,medicine ,Humans ,Point Mutation ,ddc:576.5 ,Genetic Testing ,Neurofibromatosis ,Molecular Biology ,Gene ,Genetics (clinical) ,Mutation ,Transition (genetics) ,Base Sequence ,DNA, Complementary/genetics ,General Medicine ,Exons ,Middle Aged ,medicine.disease ,Exon skipping ,RNA splicing - Published
- 1994
31. A 5178-9g→ A splice donor site mutation in intron 4 of theMEN1 gene causing multiple endocrine neoplasia type 1
- Author
-
Paul Komminoth
- Subjects
Genetics ,Cancer Research ,Splice Donor Site ,Oncology ,Mutation (genetic algorithm) ,medicine ,Cancer research ,Intron ,MEN1 ,Biology ,Multiple endocrine neoplasia ,medicine.disease ,Gene - Published
- 2000
32. Identification of a sequence likely to be required for avian retroviral packaging
- Author
-
Dennis W. Stacey and Thea Pugatschi
- Subjects
Pol genes ,Avian Leukosis Virus ,Base Sequence ,Genes, Viral ,Microinjections ,RNA Splicing ,viruses ,Chick Embryo ,DNA Restriction Enzymes ,Biology ,Virology ,Molecular biology ,Virus ,Cell Line ,Restriction site ,Titer ,Splice Donor Site ,Avian Sarcoma Viruses ,Helper virus ,Biological property ,DNA, Viral ,Animals ,RNA, Viral ,Sequence (medicine) - Abstract
Two assays have been utilized to assess the ability of avian retroviral molecules to be packaged into virus particles. Cloned viral genomic molecules were microinjected into the nuclei of chick cells infected by either a lymphoid leukosis virus or an envelope glycoprotein-deficient sarcoma virus. The titer of focus-forming virus released by injected cells, or the ratio of these to helper virus, is then used to determine packaging efficiency, although biological properties other than packaging might also effect these assays. With either assay, deletions up to 3.0 kbp introduced in the viral gag or pol genes did not affect packaging unless sequences near the SstII restriction site (approximately 150 by 3′ of the splice donor site) were deleted. Deletions differing by 2 by at the SstII site were found to express radically different packaging efficiencies.
- Published
- 1983
33. Efficient replication of full-length murine leukemia viruses modified at the dimer initiation site regions
- Author
-
Lars Aagaard, Finn Skou Pedersen, Søren Rasmussen, and Jacob Giehm Mikkelsen
- Subjects
RNA, Spliced Leader ,BALB 3T3 Cells ,Five prime untranslated region ,RNA Splicing ,viruses ,Leader region ,Molecular Sequence Data ,Encapsidation ,Virus Replication ,Splicing ,Dimer initiation site (DIS) ,Cell Line ,Mice ,Retrovirus ,Virology ,Murine leukemia virus ,Animals ,Point Mutation ,Palindromic regions ,Vector (molecular biology) ,5′ Untranslated region ,Genetics ,Kissing loop ,biology ,Base Sequence ,Virus Assembly ,RNA ,biology.organism_classification ,Stem-loop ,Leukemia Virus, Murine ,Enhancer Elements, Genetic ,Viral replication ,Packaging ,RNA splicing ,Splice donor site ,5' Untranslated Regions ,Dimerization ,Gene Deletion - Abstract
Retroviruses encapsidate two copies of full-length viral RNA molecules linked together as a dimeric genome. RNA stem loop structures harboring palindromic (or “kissing”) loop sequences constitute important cis-elements for viral dimerization known as dimer initiation sites (DIS). In murine leukemia virus (MLV), a 10-mer and a 16-mer palindrome (DIS-1 and DIS-2, respectively) located in the viral leader region mediate dimerization in vitro and affect dimer stability of vector RNA in vivo. We have investigated the effect on viral replication of introducing deletions or nucleotide substitutions within these palindromes in a full-length MLV genome. Our results demonstrate that viruses modified at the dimer initiation site regions are viable and show wild-type levels of RNA encapsidation. One mutant lacking the DIS-1 palindrome was severely impaired and displayed an increased cellular ratio of spliced versus genomic RNA that most likely contributes to the inefficient replication. The implications for development of DIS-modified retrovirus-based vectors are discussed.
- Full Text
- View/download PDF
34. [Untitled]
- Subjects
0301 basic medicine ,Genetics ,Microcephaly ,CDK5RAP2 ,business.industry ,General Medicine ,Bioinformatics ,medicine.disease ,Phenotype ,3. Good health ,03 medical and health sciences ,Exon ,030104 developmental biology ,0302 clinical medicine ,Splice Donor Site ,Pigmentary abnormalities ,Medicine ,splice ,business ,Exome ,030217 neurology & neurosurgery - Abstract
This report constitutes the first report of a cryptic exonic splice-donor site in CDK5RAP2, highlights the importance of evaluating novel splice mutations, and suggests that the phenotypic range associated with CDK5RAP2 mutations may include skin pigmentary abnormalities.
35. Complete Nucleotide Sequence of the Genome of Bovine Leukemia Virus: Its Evolutionary Relationship to Other Retroviruses
- Author
-
Sagata, Noriyuki, Yasunaga, Teruo, Tsuzuku-Kawamura, Junko, Ohishi, Kazue, Ogawa, Yasuki, and Ikawa, Yoji
- Published
- 1985
36. Aberrant Splicing of Androgen Receptor mRNA Results in Synthesis of a Nonfunctional Receptor Protein in a Patient with Androgen Insensitivity
- Author
-
Ris-Stalpers, C., Faber, P. W., Schweikert, H. U., van Rooij, H. C. J., Zegers, N. D., Hodgins, M. B., Degenhart, H. J., Trapman, J., and Brinkmann, A. O.
- Published
- 1990
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