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https://www.readbyqxmd.com/read/29103974/optimization-of-a-series-of-heterocycles-as-survival-motor-neuron-gene-transcription-enhancers
#1
Sungwoon Choi, Alyssa N Calder, Eliza H Miller, Kierstyn P Anderson, Dawid K Fiejtek, Anne Rietz, Hongxia Li, Jonathan J Cherry, Kevin M Quist, Xuechao Xing, Marcie A Glicksman, Gregory D Cuny, Christian L Lorson, Elliot A Androphy, Kevin J Hodgetts
Spinal muscular atrophy (SMA) is a neurodegenerative disorder that results from mutations in the SMN1 gene, leading to survival motor neuron (SMN) protein deficiency. One therapeutic strategy for SMA is to identify compounds that enhance the expression of the SMN2 gene, which normally only is a minor contributor to functional SMN protein production, but which is unaffected in SMA. A recent high-throughput screening campaign identified a 3,4-dihydro-4-phenyl-2(1H)-quinolinone derivative (2) that increases the expression of SMN2 by 2-fold with an EC50 = 8...
October 26, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29096367/electrochemical-immunosensors-for-the-detection-of-survival-motor-neuron-smn-protein-using-different-carbon-nanomaterials-modified-electrodes
#2
Shimaa Eissa, Nawal Alshehri, Anas M Abdel Rahman, Majed Dasouki, Khalid M Abu Salah, Mohammed Zourob
Spinal muscular atrophy is an untreatable potentially fatal hereditary disorder caused by loss-of-function mutations in the survival motor neuron (SMN) 1 gene which encodes the SMN protein. Currently, definitive diagnosis relies on the demonstration of biallelic pathogenic variants in SMN1 gene. Therefore, there is an urgent unmet need to accurately quantify SMN protein levels for screening and therapeutic monitoring of symptomatic newborn and SMA patients, respectively. Here, we developed a voltammetric immunosensor for the sensitive detection of SMN protein based on covalently functionalized carbon nanofiber-modified screen printed electrodes...
October 10, 2017: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/29091557/single-dose-gene-replacement-therapy-for-spinal-muscular-atrophy
#3
Jerry R Mendell, Samiah Al-Zaidy, Richard Shell, W Dave Arnold, Louise R Rodino-Klapac, Thomas W Prior, Linda Lowes, Lindsay Alfano, Katherine Berry, Kathleen Church, John T Kissel, Sukumar Nagendran, James L'Italien, Douglas M Sproule, Courtney Wells, Jessica A Cardenas, Marjet D Heitzer, Allan Kaspar, Sarah Corcoran, Lyndsey Braun, Shibi Likhite, Carlos Miranda, Kathrin Meyer, K D Foust, Arthur H M Burghes, Brian K Kaspar
BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease. METHODS: Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein...
November 2, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29080838/the-smn1-common-variant-c-22-dupa-in-chinese-patients-causes-spinal-muscular-atrophy-by-nonsense-mediated-mrna-decay-in-humans
#4
Bai JinLi, Qu YuJin, Cao YanYan, Yang Lan, Ge Lin, Jin YuWei, Wang Hong, Song Fang
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is mostly caused by homozygous deletion of the SMN1 gene. Approximately 5%-10% of SMA patients are believed to have SMN1 variants. c.22 dupA (p.Ser8lysfs*23) has been identified as the most frequent variant in the Chinese SMA population and to be associated with a severe phenotype. However, the exact molecular mechanism of the variant on the pathogenesis of SMA is unclear. We observed that SMN1 mRNA and the SMN protein in the peripheral blood cells of a patient with c...
October 25, 2017: Gene
https://www.readbyqxmd.com/read/29066780/survival-motor-neuron-protein-is-released-from-cells-in-exosomes-a-potential-biomarker-for-spinal-muscular-atrophy
#5
Leslie A Nash, Emily R McFall, Amanda M Perozzo, Maddison Turner, Kathy L Poulin, Yves De Repentigny, Joseph K Burns, Hugh J McMillan, Jodi Warman Chardon, Dylan Burger, Rashmi Kothary, Robin J Parks
Spinal muscular atrophy (SMA) is caused by homozygous mutation of the survival motor neuron 1 (SMN1) gene. Disease severity inversely correlates to the amount of SMN protein produced from the homologous SMN2 gene. We show that SMN protein is naturally released in exosomes from all cell types examined. Fibroblasts from patients or a mouse model of SMA released exosomes containing reduced levels of SMN protein relative to normal controls. Cells overexpressing SMN protein released exosomes with dramatically elevated levels of SMN protein...
October 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28983837/treatment-advances-in-spinal-muscular-atrophy
#6
REVIEW
Diana Bharucha-Goebel, Petra Kaufmann
PURPOSE OF REVIEW: Spinal muscular atrophy (SMA) is a genetic disorder of motor neurons in the anterior horns of the spinal cord and brainstem that results in muscle atrophy and weakness. SMA is an autosomal recessive disease linked to deletions of the SMN1 gene on chromosome 5q. Humans have a duplicate gene (SMN2) whose product can mitigate disease severity, leading to the variability in severity and age of onset of disease, and is therefore a target for drug development. RECENT FINDINGS: Advances in preclinical and clinical trials have paved the way for novel therapeutic options for SMA patients, including many currently in clinical trials...
October 6, 2017: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/28981927/-analysis-of-smn1-gene-mutations-in-78-patients-with-spinal-muscular-atrophy
#7
Jing Li, Yuling Zhu, Yixin Zhan, Yaqin Li, Menglong Chen, Liang Wang, Ruojie He, Cheng Zhang
OBJECTIVE: To explore the significance of SMN1 gene mutations among patients with spinal muscular atrophy (SMA) and the value of multiplex ligation dependent probe amplification (MLPA) for its diagnosis. METHODS: Potential mutations of the SMN1 gene were detected among 78 SMA patients with a MLPA assay. RESULTS: Homozygous deletion of SMN1 exons 7 and 8 was detected in 70 (89.7%) of all patients. Homozygous deletion of exons 7 and heterozygous deletion of exon 8 was detected in 3 patients (3...
October 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/28981879/activation-of-a-cryptic-5-splice-site-reverses-the-impact-of-pathogenic-splice-site-mutations-in-the-spinal-muscular-atrophy-gene
#8
Natalia N Singh, José Bruno Del Rio-Malewski, Diou Luo, Eric W Ottesen, Matthew D Howell, Ravindra N Singh
Spinal muscular atrophy (SMA) is caused by deletions or mutations of the Survival Motor Neuron 1 (SMN1) gene coupled with predominant skipping of SMN2 exon 7. The only approved SMA treatment is an antisense oligonucleotide that targets the intronic splicing silencer N1 (ISS-N1), located downstream of the 5' splice site (5'ss) of exon 7. Here, we describe a novel approach to exon 7 splicing modulation through activation of a cryptic 5'ss (Cr1). We discovered the activation of Cr1 in transcripts derived from SMN1 that carries a pathogenic G-to-C mutation at the first position (G1C) of intron 7...
September 15, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28977438/spinal-muscular-atrophy-antisense-oligonucleotide-therapy-opens-the-door-to-an-integrated-therapeutic-landscape
#9
Matthew J A Wood, Kevin Talbot, Melissa Bowerman
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of spinal cord motor neurons, muscle atrophy and infantile death or severe disability. It is caused by severe reduction of the ubiquitously expressed survival motor neuron (SMN) protein, owing to loss of the SMN1 gene. This would be completely incompatible with survival without the presence of a quasi-identical duplicated gene, SMN2, specific to humans. SMN2 harbours a silent point mutation that favours the production of transcripts lacking exon 7 and a rapidly degraded non-functional SMNΔ7 protein, but from which functional full length SMN protein is produced at very low levels (∼10%)...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28962115/application-of-urine-cells-in-drug-intervention-for-spinal-muscular-atrophy
#10
Qi-Jie Zhang, Xiang Lin, Jin-Jing Li, Ying-Qian Lu, Xin-Xin Guo, En-Lin Dong, Miao Zhao, Jin He, Ning Wang, Wan-Jin Chen
Spinal muscular atrophy (SMA) is a lethal childhood neurodegenerative disorder that is caused by the homozygous deletion of survival motor neuron 1 (SMN1). To date, no effective treatments are available. In the current study, urine cells taken from SMA patients were cultured and the application of patient-derived urine cells was determined in drug intervention. A total of 13 SMA patient-derived urine cell lines and 40 control cell lines were established. SMN was highly expressed in the nucleus and cytoplasm...
September 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28950212/p-val19glyfs-21-and-p-leu228-variants-in-the-survival-of-motor-neuron-1-trigger-nonsense-mediated-mrna-decay-causing-the-smn1-ptc-transcripts-degradation
#11
Yu-Jin Qu, Lin Ge, Jin-Li Bai, Yan-Yan Cao, Yu-Wei Jin, Hong Wang, Lan Yang, Fang Song
Spinal Muscular Atrophy (SMA) results from loss-of-function mutations in the survival of motor neuron 1 (SMN1) gene. Our previous research showed that 40% of variants were nonsense or frameshift variants and SMN1 mRNA levels in the patients carrying these variants were significantly decreased. Here we selected one rare variant (p.Val19Glyfs*21) and one common variant (p.Leu228*) to explore the degradation mechanism of mutant transcripts. The levels of full-length (FL)-SMN1 transcripts and SMN protein in the cell lines from the patients with these variants were both significantly reduced (p<0...
September 15, 2017: Mutation Research
https://www.readbyqxmd.com/read/28945765/in-vitro-and-in-vivo-effects-of-2-4-diaminoquinazoline-inhibitors-of-the-decapping-scavenger-enzyme-dcps-context-specific-modulation-of-smn-transcript-levels
#12
Jonathan J Cherry, Christine J DiDonato, Elliot J Androphy, Alessandro Calo, Kyle Potter, Sara K Custer, Sarah Du, Timothy L Foley, Ariamala Gopalsamy, Emily J Reedich, Susana M Gordo, William Gordon, Natalie Hosea, Lyn H Jones, Daniel K Krizay, Gregory LaRosa, Hongxia Li, Sachin Mathur, Carol A Menard, Paraj Patel, Rebeca Ramos-Zayas, Anne Rietz, Haojing Rong, Baohong Zhang, Michael A Tones
C5-substituted 2,4-diaminoquinazoline inhibitors of the decapping scavenger enzyme DcpS (DAQ-DcpSi) have been developed for the treatment of spinal muscular atrophy (SMA), which is caused by genetic deficiency in the Survival Motor Neuron (SMN) protein. These compounds are claimed to act as SMN2 transcriptional activators but data underlying that claim are equivocal. In addition it is unclear whether the claimed effects on SMN2 are a direct consequence of DcpS inhibitor or might be a consequence of lysosomotropism, which is known to be neuroprotective...
2017: PloS One
https://www.readbyqxmd.com/read/28939077/genomic-characterization-of-tobacco-nut-chewing-hpv-negative-early-stage-tongue-tumors-identify-mmp10-asa-candidate-to-predict-metastases
#13
Pawan Upadhyay, Nilesh Gardi, Sanket Desai, Pratik Chandrani, Asim Joshi, Bhaskar Dharavath, Priyanca Arora, Munita Bal, Sudhir Nair, Amit Dutt
OBJECTIVES: Nodal metastases status among early stage tongue squamous cell cancer patients plays a decisive role in the choice of treatment, wherein about 70% patients can be spared from surgery with an accurate prediction of negative pathological lymph node status. This underscores an unmet need for prognostic biomarkers to stratify the patients who are likely to develop metastases. MATERIALS AND METHODS: We performed high throughput sequencing of fifty four samples derived from HPV negative early stage tongue cancer patients habitual of chewing betel nuts, areca nuts, lime or tobacco using whole exome (n=47) and transcriptome (n=17) sequencing that were analyzed using in-house computational tools...
October 2017: Oral Oncology
https://www.readbyqxmd.com/read/28936620/osteoclast-stimulation-factor-1-ostf1-knockout-increases-trabecular-bone-mass-in-mice
#14
Matthieu Vermeren, Rodanthi Lyraki, Sachin Wani, Rannar Airik, Omar Albagha, Richard Mort, Friedhelm Hildebrandt, Toby Hurd
Osteoclast stimulation factor 1 (OSTF1) is an SH3-domain containing protein that was initially identified as a factor involved in the indirect activation of osteoclasts. It has been linked to spinal muscular atrophy in humans through its interaction with SMN1, and is one of six genes deleted in a human developmental microdeletion syndrome. To investigate the function of OSTF1, we generated an Ostf1 knockout mouse model, with exons 3 and 4 of Ostf1 replaced by a LacZ orf. Extensive X-Gal staining was performed to examine the developmental and adult expression pattern, followed by phenotyping...
September 21, 2017: Mammalian Genome: Official Journal of the International Mammalian Genome Society
https://www.readbyqxmd.com/read/28899515/the-water-extract-of-liuwei-dihuang-possesses-multi-protective-properties-on-neurons-and-muscle-tissue-against-deficiency-of-survival-motor-neuron-protein
#15
Yu-Ting Tseng, Yuh-Jyh Jong, Wei-Fang Liang, Fang-Rong Chang, Yi-Ching Lo
BACKGROUND: Deficiency of survival motor neuron (SMN) protein, which is encoded by the SMN1 and SMN2 genes, induces widespread splicing defects mainly in spinal motor neurons, and leads to spinal muscular atrophy (SMA). Currently, there is no effective treatment for SMA. Liuwei dihuang (LWDH), a traditional Chinese herbal formula, possesses multiple therapeutic benefits against various diseases via modulation of the nervous, immune and endocrine systems. Previously, we demonstrated water extract of LWDH (LWDH-WE) protects dopaminergic neurons and improves motor activity in models of Parkinson's disease...
October 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28879433/cbp-mediated-smn-acetylation-modulates-cajal-body-biogenesis-and-the-cytoplasmic-targeting-of-smn
#16
Vanesa Lafarga, Olga Tapia, Sahil Sharma, Rocio Bengoechea, Georg Stoecklin, Miguel Lafarga, Maria T Berciano
The survival of motor neuron (SMN) protein plays an essential role in the biogenesis of spliceosomal snRNPs and the molecular assembly of Cajal bodies (CBs). Deletion of or mutations in the SMN1 gene cause spinal muscular atrophy (SMA) with degeneration and loss of motor neurons. Reduced SMN levels in SMA lead to deficient snRNP biogenesis with consequent splicing pathology. Here, we demonstrate that SMN is a novel and specific target of the acetyltransferase CBP (CREB-binding protein). Furthermore, we identify lysine (K) 119 as the main acetylation site in SMN...
September 6, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28797588/longitudinal-assessments-in-discordant-twins-with-sma
#17
Marika Pane, Leonardo Lapenta, Emanuela Abiusi, Roberto de Sanctis, Marco Luigetti, Concetta Palermo, Domiziana Ranalli, Stefania Fiori, Francesco Danilo Tiziano, Eugenio Mercuri
We report longitudinal clinical and neurophysiological assessments in twins affected by spinal muscular atrophy (SMA) with discordant phenotypes. The boy had the homozygous deletion of SMN1, a typical type 1 SMA course, and died at the age of eight months. His twin sister, asymptomatic at the time of the diagnosis in her brother, had the same genetic defect but she developed clinical and electrophysiological signs of type 2 SMA. The reduction of tendon reflexes was the first clinical sign at the age of 4 months, followed within few weeks, by a mild decrement in the amplitude of the compound motor action potentials...
July 8, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/28792153/clinical-characteristics-of-spinal-muscular-atrophy-in-korea-confirmed-by-genetic-analysis
#18
Heewon Hwang, Jung Hwan Lee, Young Chul Choi
The objective of this study was to review the clinical characteristics of patients with spinal muscular atrophy and to emphasize the importance of performing genetic mutational analysis at initial patient assessment. This is a single center oriented, retrospective, and descriptive study conducted in Seoul, South Korea. Genetic mutational analysis to detect the deletion of exon 7 of the SMN1 gene on chromosome 5q13 was performed by multiplex ligation-dependent probe amplification. Clinical features, electrodiagnostic study results, muscle biopsy results, and laboratory test results were reviewed from patient medical records...
September 2017: Yonsei Medical Journal
https://www.readbyqxmd.com/read/28775379/tia1-is-a-gender-specific-disease-modifier-of-a-mild-mouse-model-of-spinal-muscular-atrophy
#19
Matthew D Howell, Eric W Ottesen, Natalia N Singh, Rachel L Anderson, Joonbae Seo, Senthilkumar Sivanesan, Elizabeth M Whitley, Ravindra N Singh
Spinal muscular atrophy (SMA) is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. The nearly identical SMN2 cannot compensate for SMN1 loss due to exon 7 skipping. The allele C (C (+/+)) mouse recapitulates a mild SMA-like phenotype and offers an ideal system to monitor the role of disease-modifying factors over a long time. T-cell-restricted intracellular antigen 1 (TIA1) regulates SMN exon 7 splicing. TIA1 is reported to be downregulated in obese patients, although it is not known if the effect is gender-specific...
August 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28768735/therapeutic-strategies-for-spinal-muscular-atrophy-smn-and-beyond
#20
REVIEW
Melissa Bowerman, Catherina G Becker, Rafael J Yáñez-Muñoz, Ke Ning, Matthew J A Wood, Thomas H Gillingwater, Kevin Talbot
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1 A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed...
August 1, 2017: Disease Models & Mechanisms
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