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S Radovic, G Dubsky De Wittenau, N Mandl, E Betto, F Curcio, M Morgante, I R Lonigro
A comparison of the individual genomes within a species demonstrates that structural variation, including copy number variation (CNV), is a major contributor to phenotypic diversity and evolutionary adaptation. CNVs lead to the under/over-expression of a gene, according to the changes in the gene dosage, which account for the development of a number of genomic disorders. Thus, the development of efficient, rapid and accurate CNV screening is of fundamental importance. We report a method that enables the simultaneous determination of the copy numbers of several different targets as well as the discrimination among highly similar/almost identical targets that differ by only one single nucleotide variant, which establishes their copy numbers...
January 2018: Journal of Biological Regulators and Homeostatic Agents
Eveline S Arnold, Kenneth H Fischbeck
Autosomal-recessive proximal spinal muscular atrophy (Werdnig-Hoffmann, Kugelberg-Welander) is caused by mutation of the SMN1 gene, and the clinical severity correlates with the number of copies of a nearly identical gene, SMN2. The SMN protein plays a critical role in spliceosome assembly and may have other cellular functions, such as mRNA transport. Cell culture and animal models have helped to define the disease mechanism and to identify targets for therapeutic intervention. The main focus for developing treatment has been to increase SMN levels, and accomplishing this with small molecules, oligonucleotides, and gene replacement has been quite...
2018: Handbook of Clinical Neurology
Eugenio Mercuri, Basil T Darras, Claudia A Chiriboga, John W Day, Craig Campbell, Anne M Connolly, Susan T Iannaccone, Janbernd Kirschner, Nancy L Kuntz, Kayoko Saito, Perry B Shieh, Már Tulinius, Elena S Mazzone, Jacqueline Montes, Kathie M Bishop, Qingqing Yang, Richard Foster, Sarah Gheuens, C Frank Bennett, Wildon Farwell, Eugene Schneider, Darryl C De Vivo, Richard S Finkel
BACKGROUND: Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). METHODS: We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274...
February 15, 2018: New England Journal of Medicine
Valeria Parente, Stefania Corti
Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families...
2018: Therapeutic Advances in Neurological Disorders
Mawaddah Ar Rochmah, Ai Shima, Nur Imma Fatimah Harahap, Emma Tabe Eko Niba, Naoya Morisada, Shinichiro Yanagisawa, Toshio Saito, Kaori Kaneko, Kayoko Saito, Ichiro Morioka, Kazumoto Iijima, Poh San Lai, Yoshihiro Bouike, Hisahide Nishio, Masakazu Shinohara
BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by a mutation in SMN1. SMA is classified into three subtypes (types 1, 2, 3) based on achieved motor milestones. Although NAIP and SMN2 are widely accepted as SMA-modifying factors, gender-related modifying factors or gender effects on the clinical phenotype are still controversial. METHODS: A total of 122 Japanese patients with SMA, of which SMN1 was homozygously deleted, were analyzed from the perspective of the achieved motor milestone, NAIP status and SMN2 copy number...
October 16, 2017: Kobe Journal of Medical Sciences
Maite Calucho, Sara Bernal, Laura Alías, Francesca March, Adoración Venceslá, Francisco J Rodríguez-Álvarez, Elena Aller, Raquel M Fernández, Salud Borrego, José M Millán, Concepción Hernández-Chico, Ivon Cuscó, Pablo Fuentes-Prior, Eduardo F Tizzano
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss or mutations in SMN1. According to age of onset, achieved motor abilities, and life span, SMA patients are classified into type I (never sit), II (never walk unaided) or III (achieve independent walking abilities). SMN2, the highly homologous copy of SMN1, is considered the most important phenotypic modifier of the disease. Determination of SMN2 copy number is essential to establish careful genotype-phenotype correlations, predict disease evolution, and to stratify patients for clinical trials...
January 11, 2018: Neuromuscular Disorders: NMD
Francesca Biagioni, Michela Ferrucci, Larisa Ryskalin, Federica Fulceri, Gloria Lazzeri, Maria Teresa Calierno, Carla L Busceti, Riccardo Ruffoli, Francesco Fornai
In the present study we evaluated the long-term effects of lithium administration to a knock-out double transgenic mouse model (Smn-/-; SMN1A2G+/-; SMN2+/+) of Spinal Muscle Atrophy type III (SMA-III). This model is characterized by very low levels of the survival motor neuron protein, slow disease progression and motor neuron loss, which enables to detect disease-modifying effects at delayed time intervals. Lithium administration attenuates the decrease in motor activity and provides full protection from motor neuron loss occurring in SMA-III mice, throughout the disease course...
December 1, 2017: Archives Italiennes de Biologie
Hannah K Shorrock, Thomas H Gillingwater, Ewout J N Groen
Spinal muscular atrophy (SMA) is a neurodegenerative disease primarily characterized by a loss of spinal motor neurons, leading to progressive paralysis and premature death in the most severe cases. SMA is caused by homozygous deletion of the survival motor neuron 1 (SMN1) gene, leading to low levels of SMN protein. However, a second SMN gene (SMN2) exists, which can be therapeutically targeted to increase SMN levels. This has recently led to the first disease-modifying therapy for SMA gaining formal approval from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)...
January 29, 2018: Drugs
Ingo D Meier, Michael P Walker, A Gregory Matera
Gemin4 is a member of the Survival Motor Neuron (SMN) protein complex, which is responsible for the assembly and maturation of Sm-class small nuclear ribonucleoproteins (snRNPs). In metazoa, Sm snRNPs are assembled in the cytoplasm and subsequently imported into the nucleus. We previously showed that the SMN complex is required for snRNP import in vitro, although it remains unclear which specific components direct this process. Here, we report that Gemin4 overexpression drives SMN and the other Gemin proteins from the cytoplasm into the nucleus...
January 25, 2018: Biology Open
Gamze Bora, Şulenur Subaşı-Yıldız, Ayşe Yeşbek-Kaymaz, Numan Bulut, İpek Alemdaroğlu, Öznur Tunca-Yılmaz, Haluk Topaloğlu, Aynur Ayşe Karaduman, Hayat Erdem-Yurter
Exercise studies in neuromuscular diseases like spinal muscular atrophy (SMA), a devastating disease caused by survival of motor neuron 1 ( SMN1) gene mutations, are drawing attention due to its beneficial effects. In this study, we presented a constructed arm cycling exercise protocol and evaluated the benefits on SMA patients. Five SMA type II patients performed 12 weeks of supervised arm cycling exercise. The physical functions were evaluated together with the SMN2 copy numbers, SMN protein levels, insulin-like growth factor 1(IGF1) and binding protein 3 (IGFBP3) levels...
January 1, 2018: Journal of Child Neurology
Agnese Ramirez, Sebastiano G Crisafulli, Mafalda Rizzuti, Nereo Bresolin, Giacomo P Comi, Stefania Corti, Monica Nizzardo
Spinal muscular atrophy (SMA) is an autosomal-recessive childhood motor neuron disease and the main genetic cause of infant mortality. SMA is caused by deletions or mutations in the survival motor neuron 1 ( SMN1 ) gene, which results in SMN protein deficiency. Only one approved drug has recently become available and allows for the correction of aberrant splicing of the paralogous SMN2 gene by antisense oligonucleotides (ASOs), leading to production of full-length SMN protein. We have already demonstrated that a sequence of an ASO variant, Morpholino (MO), is particularly suitable because of its safety and efficacy profile and is both able to increase SMN levels and rescue the murine SMA phenotype...
January 6, 2018: International Journal of Molecular Sciences
Astrid Pechmann, Thorsten Langer, Sabine Wider, Janbernd Kirschner
BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder mainly characterized by proximal muscle weakness. There have been enormous advances in therapeutic development with the possibility to influence the clinical course of the disease. Nusinersen is the first approved drug to treat SMA. It is administered intrathecally and acts as splicing modifier of the SMN2 gene. METHODS: Lumbar punctures were performed using a standardized protocol. To evaluate safety and feasibility of the intrathecal treatment, vital signs and the need for sedation, analgesia or mechanical ventilation during the procedure were monitored...
January 2018: European Journal of Paediatric Neurology: EJPN
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
Roberto De Sanctis, Marika Pane, Giorgia Coratti, Concetta Palermo, Daniela Leone, Maria Carmela Pera, Emanuela Abiusi, Stefania Fiori, Nicola Forcina, Lavinia Fanelli, Simona Lucibello, Elena S Mazzone, Francesco Danilo Tiziano, Eugenio Mercuri
The advent of clinical trials has highlighted the need for natural history studies reporting disease progression in type 1 spinal muscular atrophy. The aim of this study was to assess functional changes using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale in a cohort of type 1 infants. Nutritional and respiratory longitudinal data were also recorded. Patients were classified according to the severity of the phenotype and age of onset. SMN2 copies were also assessed...
January 2018: Neuromuscular Disorders: NMD
Kelsey M Gray, Kevin A Kaifer, David Baillat, Ying Wen, Thomas R Bonacci, Allison D Ebert, Amanda C Raimer, Ashlyn M Spring, Sara Ten Have, Jacqueline J Glascock, Kushol Gupta, Gregory D Van Duyne, Michael J Emanuele, Angus I Lamond, Eric J Wagner, Christian L Lorson, A Gregory Matera
Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1 Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of SMN isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCF(Slmb) ubiquitin E3 ligase complex as a novel SMN binding partner. SCF(Slmb) interacts with a phospho-degron embedded within the human and fruitfly SMN YG-box oligomerization domains...
November 22, 2017: Molecular Biology of the Cell
Stephen J Kolb, Christopher S Coffey, Jon W Yankey, Kristin Krosschell, W David Arnold, Seward B Rutkove, Kathryn J Swoboda, Sandra P Reyna, Ai Sakonju, Basil T Darras, Richard Shell, Nancy Kuntz, Diana Castro, Julie Parsons, Anne M Connolly, Claudia A Chiriboga, Craig McDonald, W Bryan Burnette, Klaus Werner, Mathula Thangarajh, Perry B Shieh, Erika Finanger, Merit E Cudkowicz, Michelle M McGovern, D Elizabeth McNeil, Richard Finkel, Susan T Iannaccone, Edward Kaye, Allison Kingsley, Samantha R Renusch, Vicki L McGovern, Xueqian Wang, Phillip G Zaworski, Thomas W Prior, Arthur H M Burghes, Amy Bartlett, John T Kissel
OBJECTIVE: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. METHODS: A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months...
December 2017: Annals of Neurology
Manaswini Sivaramakrishnan, Kathleen D McCarthy, Sébastien Campagne, Sylwia Huber, Sonja Meier, Angélique Augustin, Tobias Heckel, Hélène Meistermann, Melanie N Hug, Pascale Birrer, Ahmed Moursy, Sarah Khawaja, Roland Schmucki, Nikos Berntenis, Nicolas Giroud, Sabrina Golling, Manuel Tzouros, Balazs Banfai, Gonzalo Duran-Pacheco, Jens Lamerz, Ying Hsiu Liu, Thomas Luebbers, Hasane Ratni, Martin Ebeling, Antoine Cléry, Sergey Paushkin, Adrian R Krainer, Frédéric H-T Allain, Friedrich Metzger
Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the splicing deficit of the SMN2 (survival of motor neuron 2) gene have been identified and these molecules are moving towards a potential therapy for spinal muscular atrophy (SMA). Here by using a combination of RNA splicing, transcription, and protein chemistry techniques, we show that these molecules directly bind to two distinct sites of the SMN2 pre-mRNA, thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes...
November 14, 2017: Nature Communications
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...
December 1, 2017: Bioorganic & Medicinal Chemistry Letters
Richard S Finkel, Eugenio Mercuri, Basil T Darras, Anne M Connolly, Nancy L Kuntz, Janbernd Kirschner, Claudia A Chiriboga, Kayoko Saito, Laurent Servais, Eduardo Tizzano, Haluk Topaloglu, Már Tulinius, Jacqueline Montes, Allan M Glanzman, Kathie Bishop, Z John Zhong, Sarah Gheuens, C Frank Bennett, Eugene Schneider, Wildon Farwell, Darryl C De Vivo
BACKGROUND: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODS: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy...
November 2, 2017: New England Journal of Medicine
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
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