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Exon skipping

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https://www.readbyqxmd.com/read/29684050/intronic-pah-gene-mutations-cause-a-splicing-defect-by-a-novel-mechanism-involving-u1snrnp-binding-downstream-of-the-5-splice-site
#1
Ainhoa Martínez-Pizarro, Maja Dembic, Belén Pérez, Brage S Andresen, Lourdes R Desviat
Phenylketonuria (PKU), one of the most common inherited diseases of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene. Recently, PAH exon 11 was identified as a vulnerable exon due to a weak 3' splice site, with different exonic mutations affecting exon 11 splicing through disruption of exonic splicing regulatory elements. In this study, we report a novel intron 11 regulatory element, which is involved in exon 11 splicing, as revealed by the investigated pathogenic effect of variants c...
April 23, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29681093/low-level-expression-of-epg5-leads-to-an-attenuated-vici-syndrome-phenotype
#2
Megan A Waldrop, Felecia Gumienny, Daniel Boue, Emily de Los Reyes, Richard Shell, Robert B Weiss, Kevin M Flanigan
Vici syndrome is a multisystem disorder characterized by agenesis of the corpus callosum, oculocutaneous hypopigmentation, cataracts, cardiomyopathy, combined immunodeficiency, failure to thrive, profound developmental delay, and acquired microcephaly. Most individuals are severely affected and have a markedly reduced life span. Here we describe an 8-year-old boy with a history of developmental delay, agenesis of the corpus callosum, failure to thrive, myopathy, and well-controlled epilepsy. He was initially diagnosed with a mitochondrial disorder, based in part upon nonspecific muscle biopsy findings, but mitochondrial DNA mutation analysis revealed no mutations...
May 2018: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29678492/hmga1a-induces-alternative-splicing-of-estrogen-receptor-alpha-in-mcf-7-human-breast-cancer-cells
#3
Kenji Ohe, Shinsuke Miyajima, Tomoko Tanaka, Yuriko Hamaguchi, Yoshihiro Harada, Yuta Horita, Yuki Beppu, Fumiaki Ito, Takafumi Yamasaki, Hiroki Terai, Masayoshi Mori, Yusuke Murata, Makito Tanabe, Kenji Ashida, Munechika Enjoji, Toshihiko Yanase, Nobuhiro Harada, Toshiaki Utsumi, Akila Mayeda
The high-mobility group A protein 1a (HMGA1a) protein is known as an oncogene whose expression level in cancer tissue correlates with the malignant potential, and known as a component of senescence-related structures connecting it to tumor suppressor networks in fibroblasts. HMGA1 protein binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. Our previous studies have shown that sequence-specific RNA-binding of HMGA1a induces exon-skipping of Presenilin-2 exon 5 in sporadic Alzheimer disease...
April 17, 2018: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29676859/a-novel-splicing-mutation-of-ectodysplasin-a-gene-responsible-for-hypohidrotic-ectodermal-dysplasia
#4
Guannan Liu, Xin Wang, Man Qin, Lisha Sun, Junxia Zhu
Hypohidrotic ectodermal dysplasia (HED) is characterized by hypohidrosis, hypodontia, sparse hair and characteristic facial features. This condition is caused by an ectodysplasin A (EDA) gene mutation. In this study, we examined two HED pedigrees and investigated the molecular genetics of the defect. Direct sequencing analysis revealed a previously unidentified mutation in the EDA splice donor site (c.526+1G>A). The function of the mutant EDA gene was predicted through online investigations and subsequently confirmed by splicing analysis in vitro...
April 20, 2018: Oral Diseases
https://www.readbyqxmd.com/read/29672841/mutant-myo1f-alters-the-mitochondrial-network-and-induces-tumor-proliferation-in-thyroid-cancer
#5
Chiara Diquigiovanni, Christian Bergamini, Cecilia Evangelisti, Federica Isidori, Andrea Vettori, Natascia Tiso, Francesco Argenton, Anna Costanzini, Luisa Iommarini, Hima Anbunathan, Uberto Pagotto, Andrea Repaci, Giulia Babbi, Rita Casadio, Giorgio Lenaz, Kerry J Rhoden, Anna Maria Porcelli, Romana Fato, Anne Bowcock, Marco Seri, Giovanni Romeo, Elena Bonora
Familial aggregation is a significant risk factor for the development of thyroid cancer and Familial Non-Medullary Thyroid Cancer (FNMTC) accounts for 5-7% of all NMTC. Whole Exome Sequencing analysis in the family affected by FNMTC with oncocytic features where our group previously identified a predisposing locus on chromosome 19p13.2, revealed a novel heterozygous mutation (c.400G>A, NM_012335; p.Gly134Ser) in exon 5 of MYO1F, mapping to the linkage locus. In the thyroid FRTL-5 cell model stably expressing the mutant MYO1F p...
April 19, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29672717/antisense-oligonucleotides-correct-the-familial-dysautonomia-splicing-defect-in-ikbkap-transgenic-mice
#6
Rahul Sinha, Young Jin Kim, Tomoki Nomakuchi, Kentaro Sahashi, Yimin Hua, Frank Rigo, C Frank Bennett, Adrian R Krainer
Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder caused by a point mutation in the IKBKAP gene that results in defective splicing of its pre-mRNA. The mutation weakens the 5' splice site of exon 20, causing this exon to be skipped, thereby introducing a premature termination codon. Though detailed FD pathogenesis mechanisms are not yet clear, correcting the splicing defect in the relevant tissue(s), thus restoring normal expression levels of the full-length IKAP protein, could be therapeutic...
April 17, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29669851/systemic-administration-of-the-antisense-oligonucleotide-ns-065-ncnp-01-for-skipping-of-exon-53-in-patients-with-duchenne-muscular-dystrophy
#7
Hirofumi Komaki, Tetsuya Nagata, Takashi Saito, Satoru Masuda, Eri Takeshita, Masayuki Sasaki, Hisateru Tachimori, Harumasa Nakamura, Yoshitsugu Aoki, Shin'ichi Takeda
Duchenne muscular dystrophy (DMD) is a lethal hereditary muscle disease caused by mutations in the gene encoding the muscle protein dystrophin. These mutations result in a shift in the open reading frame leading to loss of the dystrophin protein. Antisense oligonucleotides (ASOs) that induce exon skipping correct this frame shift during pre-mRNA splicing and partially restore dystrophin expression in mouse and dog models. We conducted a phase 1, open-label, dose-escalation clinical trial to determine the safety, pharmacokinetics, and activity of NS-065/NCNP-01, a morpholino ASO that enables skipping of exon 53...
April 18, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29665865/integrative-analysis-reveals-functional-and-regulatory-roles-of-h3k79me2-in-mediating-alternative-splicing
#8
Tianbao Li, Qi Liu, Nick Garza, Steven Kornblau, Victor X Jin
BACKGROUND: Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers. METHODS: In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3' splice site (A3SS)...
April 17, 2018: Genome Medicine
https://www.readbyqxmd.com/read/29663667/a-novel-splice-site-variant-in-itpr1-gene-underlying-recessive-gillespie-syndrome
#9
Leda Paganini, Chiara Pesenti, Donatella Milani, Laura Fontana, Silvia Motta, Silvia Maria Sirchia, Giulietta Scuvera, Paola Marchisio, Susanna Esposito, Claudia Maria Cinnante, Silvia Maria Tabano, Monica Rosa Miozzo
Gillespie syndrome (GLSP) is a rare congenital disorder characterized by partial aniridia, hypotonia, progressive cerebellar hypoplasia, nonprogressive ataxia, and intellectual disability. All causative variants to date affect the central or the 3'-terminal domains of ITPR1 gene and exhibit autosomal recessive or dominant inheritance pattern. We investigated by exome sequencing the molecular cause of GLSP in a family composed by consanguineous healthy parents, two affected siblings and one healthy son. We found the novel splice site variant c...
April 16, 2018: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29628304/targeting-amyloid-%C3%AE-precursor-protein-app-splicing-with-antisense-oligonucleotides-reduces-toxic-amyloid-%C3%AE-production
#10
Jennifer L Chang, Anthony J Hinrich, Brandon Roman, Michaela Norrbom, Frank Rigo, Robert A Marr, Eric M Norstrom, Michelle L Hastings
Alterations in amyloid beta precursor protein (APP) have been implicated in cognitive decline in Alzheimer's disease (AD), which is accelerated in Down syndrome/Trisomy 21 (DS/TS21), likely due to the extra copy of the APP gene, located on chromosome 21. Proteolytic cleavage of APP generates amyloid-β (Aβ) peptide, the primary component of senile plaques associated with AD. Reducing Aβ production is predicted to lower plaque burden and mitigate AD symptoms. Here, we designed a splice-switching antisense oligonucleotide (SSO) that causes skipping of the APP exon that encodes proteolytic cleavage sites required for Aβ peptide production...
March 6, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29625109/generation-of-splice-switching-oligonucleotides-targeting-the-cockayne-syndrome-group-b-gene-product-in-order-to-change-the-diseased-cell-state
#11
Yooksil Sin, Futaba Makimura, Masafumi Saijo, Satoshi Obika
Cockayne syndrome (CS) is a severe disorder with no effective treatment. The Cockayne syndrome group B (CSB) gene is one gene responsible for CS and also causes UV sensitive syndrome (UVS S), a disorder that causes mild symptoms. How the CSB gene determines a patient's fate is unknown, but one intriguing point is that in UVS S patient cell, there are nonsense mutations in both alleles at the same position in each upstream region of the PiggyBac transposable element derived 3 (PGBD3) inserted region. In contrast, in CS patient cells, there is at least one allele with several mutations downstream of the PGBD3 inserted region, or there are homozygous mutations in exon 1...
April 3, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29621416/c-met-inhibitors-for-advanced-non-small-cell-lung-cancer
#12
Giulia Pasquini, Giuseppe Giaccone
The role of the c-mesenchymal-epithelial transition factor (c-MET) signaling pathway in tumor progression and invasion has been extensively studied. C-MET inhibitors have shown anti-tumor activity in NSCLC both in preclinical and in clinical trials. However, given the molecular heterogeneity of NSCLC, it is likely that only a specific subset of NSCLC patients will benefit from c-MET inhibitors. Emerging data also suggest that MET inhibitors in combination with EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) may have a role in therapy for both EGFR-TKI resistant and EGFR-TKI naïve patients...
April 2018: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29615807/an-intronic-mutation-in-chd7-creates-a-cryptic-splice-site-causing-aberrant-splicing-in-a-mouse-model-of-charge-syndrome
#13
Jacqueline M Ogier, Benedicta D Arhatari, Marina R Carpinelli, Bradley K McColl, Michael A Wilson, Rachel A Burt
Alternate splicing is a critical regulator of gene expression in eukaryotes, however genetic mutations can cause erroneous splicing and disease. Most recorded splicing disorders are caused by mutations of splice donor/acceptor sites, however intronic mutations can affect splicing. Clinical exome analyses largely ignore intronic sequence, limiting the detection of mutations to within coding regions. We describe 'Trooper', a novel mouse model of CHARGE syndrome harbouring a pathogenic point mutation in Chd7. The mutation is 18 nucleotides upstream of exon 10 and creates a cryptic acceptor site, causing exon skipping and partial intron retention...
April 3, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29615706/analysis-of-the-camkii%C3%AE-and-%C3%AE-splice-variant-distribution-among-brain-regions-reveals-isoform-specific-differences-in-holoenzyme-formation
#14
Sarah G Cook, Ashley M Bourke, Heather O'Leary, Vincent Zaegel, Erika Lasda, Janna Mize-Berge, Nidia Quillinan, Chandra L Tucker, Steven J Coultrap, Paco S Herson, K Ulrich Bayer
Four CaMKII isoforms are encoded by distinct genes, and alternative splicing within the variable linker-region generates additional diversity. The α and β isoforms are largely brain-specific, where they mediate synaptic functions underlying learning, memory and cognition. Here, we determined the α and β splice-variant distribution among different mouse brain regions. Surprisingly, the nuclear variant αB was detected in all regions, and even dominated in hypothalamus and brain stem. For CaMKIIβ, the full-length variant dominated in most regions (with higher amounts of minor variants again seen in hypothalamus and brain stem)...
April 3, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29598826/the-complexity-of-titin-splicing-pattern-in-human-adult-skeletal-muscles
#15
Marco Savarese, Per Harald Jonson, Sanna Huovinen, Lars Paulin, Petri Auvinen, Bjarne Udd, Peter Hackman
BACKGROUND: Mutations in the titin gene (TTN) cause a large spectrum of diseases affecting skeletal and/or cardiac muscle. TTN includes 363 coding exons, a repeated region with a high degree of complexity, isoform-specific elements, and metatranscript-only exons thought to be expressed only during fetal development. Although three main classes of isoforms have been described so far, alternative splicing events (ASEs) in different tissues or in different developmental and physiological states have been reported...
March 29, 2018: Skeletal Muscle
https://www.readbyqxmd.com/read/29589097/an-intronic-vntr-affects-splicing-of-abca7-and-increases-risk-of-alzheimer-s-disease
#16
Arne De Roeck, Lena Duchateau, Jasper Van Dongen, Rita Cacace, Maria Bjerke, Tobi Van den Bossche, Patrick Cras, Rik Vandenberghe, Peter P De Deyn, Sebastiaan Engelborghs, Christine Van Broeckhoven, Kristel Sleegers
Mutations leading to premature termination codons in ATP-Binding Cassette Subfamily A Member 7 (ABCA7) are high penetrant risk factors of Alzheimer's disease (AD). The influence of other genetic variants in ABCA7 and downstream functional mechanisms, however, is poorly understood. To address this knowledge gap, we investigated tandem repetitive regions in ABCA7 in a Belgian cohort of 1529 AD patients and control individuals and identified an intronic variable number tandem repeat (VNTR). We observed strong association between VNTR length and a genome-wide associated signal for AD in the ABCA7 locus...
March 27, 2018: Acta Neuropathologica
https://www.readbyqxmd.com/read/29581631/dystrophin-exon-29-nonsense-mutations-cause-a-variably-mild-phenotype
#17
Rebecca S Moore, Sandya Tirupathi, Brian Herron, Andrew Sands, Patrick J Morrison
Background: Nonsense mutations in the dystrophin gene usually result in a severe Duchenne muscular dystrophy phenotype. Findings: We describe a 7-year-old boy with a rare pathogenic mutation in exon 29 c.3940C>T p.(Arg1314Ter) resulting in exon skipping, in turn rescuing the phenotype from a severe Duchenne type to a milder Becker muscular dystrophy type. No adults have been described with this mutation to date. Conclusions: Exon skipping of exon 29 results in a higher level of functional dystrophin...
September 2017: Ulster Medical Journal
https://www.readbyqxmd.com/read/29568967/novel-msh2-splice-site-mutation-in-a-young-patient-with-lynch-syndrome
#18
Raffaella Liccardo, Marina De Rosa, Paola Izzo, Francesca Duraturo
Lynch Syndrome (LS) is associated with germline mutations in one of the mismatch repair (MMR) genes, including MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6, PMS1 homolog 2, mismatch repair system component (PMS2), MLH3 and MSH3. The mutations identified in MMR genes are point mutations or large rearrangements. The point mutations are certainly pathogenetic whether they determine formation of truncated protein. The mutations that arise in splice sites are classified as 'likely pathogenic' variants. In the present study, a novel splicing mutation was identified, (named c...
March 15, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29568077/cellular-response-to-persistent-foot-and-mouth-disease-virus-infection-is-linked-to-specific-types-of-alterations-in-the-host-cell-transcriptome
#19
Lingling Han, Xiu Xin, Hailong Wang, Jiadai Li, Yao Hao, Mingzhen Wang, Congyi Zheng, Chao Shen
Food-and-mouth disease virus (FMDV) is a highly contagious virus that seriously threatens the development of animal husbandry. Although persistent FMDV infection can dramatically worsen the situation, the mechanisms involved in persistent FMDV infection remain unclear. In the present study, we identified the presence of evolved cells in the persistently FMDV-infected cell line. These cells exhibited resistance to the parent FMDV and re-established persistent infection when infected with FMDV-Op (virus supernatant of persistent infection cell lines), emphasizing the decisive role of evolved host cells in the establishment of persistent FMDV infection...
March 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29568001/dysosteosclerosis-is-also-caused-by-tnfrsf11a-mutation
#20
Long Guo, Nursel H Elcioglu, Ozge K Karalar, Mert O Topkar, Zheng Wang, Yuma Sakamoto, Naomichi Matsumoto, Noriko Miyake, Gen Nishimura, Shiro Ikegawa
Dysosteosclerosis (DOS) is a form of sclerosing bone disease characterized by irregular osteosclerosis and platyspondyly. Its mode of inheritance is autosomal recessive. SLC29A3 mutations have been reported as the causal gene in two DOS families, however, genetic heterogeneity has been suggested. By whole-exome sequencing in a Turkish patient with DOS, we found a novel splice-site mutation in TNFRSF11A. TNFRSF11A mutations have previously been reported in two autosomal dominant diseases (osteolysis, familial expansile and Paget disease of bone 2, early-onset) and an autosomal recessive disease (osteopetrosis, autosomal recessive 7)...
March 22, 2018: Journal of Human Genetics
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