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Sara K Custer, Timra D Gilson, Hongxia Li, A Gary Todd, Jacob W Astroski, Hai Lin, Yunlong Liu, Elliot J Androphy
Spinal muscular atrophy (SMA) is an intractable neurodegenerative disease afflicting 1 in 6-10,000 live births. One of the key functions of the SMN protein is regulation of spliceosome assembly. Reduced levels of the SMN protein that are observed in SMA have been shown to result in aberrant mRNA splicing. SMN-dependent mis-spliced transcripts in motor neurons may cause stresses that are particularly harmful and may serve as potential targets for the treatment of motor neuron disease or as biomarkers in the SMA patient population...
2016: PloS One
Alison K Thomson, Eilidh Somers, Rachael A Powis, Hannah K Shorrock, Kelley Murphy, Kathryn J Swoboda, Thomas H Gillingwater, Simon H Parson
Spinal muscular atrophy (SMA), traditionally described as a predominantly childhood form of motor neurone disease, is the leading genetic cause of infant mortality. Although motor neurones are undoubtedly the primary affected cell type, the severe infantile form of SMA (Type I SMA) is now widely recognised to represent a multisystem disorder where a variety of organs and systems in the body are also affected. Here, we report that the spleen is disproportionately small in the 'Taiwanese' murine model of severe SMA (Smn(-/-) ;SMN2(tg/0) ), correlated to low levels of cell proliferation and increased cell death...
October 11, 2016: Journal of Anatomy
Maria G Kier, Merete K Hansen, Jakob Lauritsen, Mette S Mortensen, Mikkel Bandak, Mads Agerbaek, Niels V Holm, Susanne O Dalton, Klaus K Andersen, Christoffer Johansen, Gedske Daugaard
Importance: Patients given systemic treatment for testicular germ cell cancer (GCC) are at increased risk for a second malignant neoplasm (SMN). Previous studies on SMN and causes of death lacked information on the exact treatment applied or were based on patients receiving former treatment options. Objective: To evaluate the treatment-specific risks for SMN and death in a nationwide population-based cohort of patients with GCC treated with current standard regimens...
October 6, 2016: JAMA Oncology
Rachael A Powis, Evangelia Karyka, Penelope Boyd, Julien Côme, Ross A Jones, Yinan Zheng, Eva Szunyogova, Ewout J N Groen, Gillian Hunter, Derek Thomson, Thomas M Wishart, Catherina G Becker, Simon H Parson, Cécile Martinat, Mimoun Azzouz, Thomas H Gillingwater
The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA...
July 21, 2016: JCI Insight
Eva Szunyogova, Haiyan Zhou, Gillian K Maxwell, Rachael A Powis, Muntoni Francesco, Thomas H Gillingwater, Simon H Parson
Spinal Muscular Atrophy (SMA) is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Decreased levels of, cell-ubiquitous, SMN protein is associated with a range of systemic pathologies reported in severe patients. Despite high levels of SMN protein in normal liver, there is no comprehensive study of liver pathology in SMA. We describe failed liver development in response to reduced SMN levels, in a mouse model of severe SMA. The SMA liver is dark red, small and has: iron deposition; immature sinusoids congested with blood; persistent erythropoietic elements and increased immature red blood cells; increased and persistent megakaryocytes which release high levels of platelets found as clot-like accumulations in the heart...
October 4, 2016: Scientific Reports
L Casagranda, M Oriol, F Freycon, D Frappaz, Y Bertrand, C Bergeron, D Plantaz, J L Stephan, C Freycon, F Gomez, C Berger, B Trombert-Paviot
From a population-based cohort of cases of first cancers diagnosed between 1987 and 2004, before the patient's age of 15 years, the authors conducted a nested case-control study, matching 64 patients who experienced a second malignant neoplasm (SMN) with 190 controls. SMNs comprised 10 leukemia or myelodysplastic syndromes, 5 lymphomas induced by Epstein-Barr virus after allograft, and 49 solid tumors, including mainly 25 carcinomas (17 of the thyroid), 9 bone sarcomas, and 7 central nervous system (CNS) tumors...
September 29, 2016: Pediatric Hematology and Oncology
Amy Sherborne, Vincent Lavergne, Katharine Yu, Leah Lee, Philip Davidson, Tali Mazor, Ivan V Smirnov, Andrew E Horvai, Mignon Loh, Steven G Dubois, Robert Goldsby, Joseph P Neglia, Sue Hammond, Leslie L Robison, Rosanna Wustrack, Joseph F Costello, Alice Nakamura, Kevin M Shannon, Smita Bhatia, Jean L Nakamura
PURPOSE: Second malignant neoplasms (SMNs) are severe late complications that occur in pediatric cancer survivors exposed to radiotherapy and other genotoxic treatments. To characterize the mutational landscape of treatment-induced sarcomas and to identify candidate SMN-predisposing variants we analyzed germline and SMN tumor samples from pediatric cancer survivors. EXPERIMENTAL DESIGN: We performed whole exome sequencing (WES) and RNA sequencing on radiation-induced sarcomas arising from two pediatric cancer survivors...
September 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jordan A Holmes, Bhishamjit S Chera, David J Brenner, Igor Shuryak, Adam K Wilson, Misty Lehman-Davis, David V Fried, Vivek Somasundaram, Jun Lian, Tim Cullip, Lawrence B Marks
PURPOSE: To quantify the risk of radiation-induced second malignancies (SMN) in pediatric patients receiving craniospinal irradiation (CSI) either with 3-dimensional conformal radiation therapy (Conv CSI) or tomotherapy helical intensity modulated radiation therapy (Tomo CSI). METHODS AND MATERIALS: A novel predictive model that accounts for short- and long-term carcinogenesis was incorporated into our institutional treatment planning system to quantify the lifetime risk of SMN in incidentally irradiated organs...
July 8, 2016: Practical Radiation Oncology
Nicole Armbruster, Annalisa Lattanzi, Matthieu Jeavons, Laetitia Van Wittenberghe, Bernard Gjata, Thibaut Marais, Samia Martin, Alban Vignaud, Thomas Voit, Fulvio Mavilio, Martine Barkats, Ana Buj-Bello
Spinal muscular atrophy (SMA) is an autosomal recessive disease of variable severity caused by mutations in the SMN1 gene. Deficiency of the ubiquitous SMN function results in spinal cord α-motor neuron degeneration and proximal muscle weakness. Gene replacement therapy with recombinant adeno-associated viral (AAV) vectors showed therapeutic efficacy in several animal models of SMA. Here, we report a study aimed at analyzing the efficacy and biodistribution of a serotype-9, self-complementary AAV vector expressing a codon-optimized human SMN1 coding sequence (coSMN1) under the control of the constitutive phosphoglycerate kinase (PGK) promoter in neonatal SMNΔ7 mice, a severe animal model of the disease...
2016: Molecular Therapy. Methods & Clinical Development
Amanda C Raimer, Kelsey M Gray, A Gregory Matera
Survival Motor Neuron (SMN) protein localizes to both the nucleus and the cytoplasm. Cytoplasmic SMN is diffusely localized in large oligomeric complexes with core member proteins, called Gemins. Biochemical and cell biological studies have demonstrated that the SMN complex is required for the cytoplasmic assembly and nuclear transport of Sm-class ribonucleoproteins (RNPs). Nuclear SMN accumulates with spliceosomal small nuclear (sn)RNPs in Cajal bodies, sub-domains involved in multiple facets of snRNP maturation...
September 20, 2016: RNA Biology
Li Lin, Wei Ming Wang, Xiao Xia Pan, Jing Xu, Chen Ni Gao, Wen Zhang, Hong Ren, Jing Yuan Xie, Pin Yan Shen, Yao Wen Xu, Li Yan Ni, Nan Chen
Anti-M-type phospholipase A2 receptor (anti-PLA2R) is a widely accepted biomarker for clinical idiopathic membranous neurophathy (IMN). However, its ability to differentiate between IMN and secondary MN (SMN) is controversial. The objective of this study was to assess clinical MN biomarkers in blood, tissue and urine samples from Chinese patients. In total, 195 MN patients and 70 patients with other glomerular diseases were prospectively enrolled in the study. Participants were followed up for average of 17 months (range 3-39 months)...
September 13, 2016: Oncotarget
Shi-Qi Yang, Zhi-Peng Xu, Ying Xiong, Ya-Feng Zhan, Lin-Ying Guo, Shun Zhang, Ri-Feng Jiang, Yi-Hao Yao, Yuan-Yuan Qin, Jian-Zhi Wang, Yong Liu, Wen-Zhen Zhu
Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment. We investigated whether alterations of intranetwork and internetwork functional connectivity with T2DM progression exist, by using resting-state functional MRI. MRI data were analysed from 19 T2DM patients with normal cognition (DMCN) and 19 T2DM patients with cognitive impairment (DMCI), 19 healthy controls (HC). Functional connectivity among 36 previously well-defined brain regions which consisted of 5 resting-state network (RSN) systems [default mode network (DMN), dorsal attention network (DAN), control network (CON), salience network (SAL) and sensorimotor network (SMN)] was investigated at 3 levels (integrity, network and connectivity)...
2016: Scientific Reports
Suzan M Hammond, Gareth Hazell, Fazel Shabanpoor, Amer F Saleh, Melissa Bowerman, James N Sleigh, Katharina E Meijboom, Haiyan Zhou, Francesco Muntoni, Kevin Talbot, Michael J Gait, Matthew J A Wood
The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
Sara Oliván, Ana C Calvo, Amaya Rando, Mireia Herrando-Grabulosa, Raquel Manzano, Pilar Zaragoza, Eduardo F Tizzano, Jose Aquilera, Rosario Osta
Spinal muscular atrophy (SMA) is a hereditary childhood disease that causes paralysis and progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. Nowadays there are no effective therapies available to treat patients with SMA, so our aim was to test whether the non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC), which exhibits neurotrophic properties, might have a therapeutic role or benefit in SMA...
2016: Frontiers in Molecular Neuroscience
Manfred S Weiss, Kay Diederichs, Randy J Read, Santosh Panjikar, Gregory D Van Duyne, A Gregory Matera, Utz Fischer, Clemens Grimm
A recent publication by Seng et al. in this journal reports the crystallographic structure of refolded, full-length SMN protein and two disease-relevant derivatives thereof. Here, we would like to suggest that at least two of the structures reported in that study are incorrect. We present evidence that one of the associated crystallographic datasets is derived from a crystal of the bacterial Sm-like protein Hfq and that a second dataset is derived from a crystal of the bacterial Gab protein. Both proteins are frequent contaminants of bacterially overexpressed proteins which might have been co-purified during metal affinity chromatography...
August 29, 2016: Human Molecular Genetics
Rocío Tejero, Mario Lopez-Manzaneda, Saravanan Arumugam, Lucía Tabares
Spinal muscular atrophy (SMA) is the most frequent genetic cause of infant mortality. The disease is characterized by progressive muscle weakness and paralysis of axial and proximal limb muscles. It is caused by homozygous loss or mutation of the SMN1 gene, which codes for the Survival Motor Neuron (SMN) protein. In mouse models of the disease, neurotransmitter release is greatly impaired, but the molecular mechanisms of the synaptic dysfunction and the basis of the selective muscle vulnerability are unknown...
August 29, 2016: Human Molecular Genetics
Kelly E Huibregtse, Kieuhoa T Vo, Steven G DuBois, Stephanie Fetzko, John Neuhaus, Vandana Batra, John M Maris, Brian Weiss, Araz Marachelian, Greg A Yanik, Katherine K Matthay
Several reports of second malignant neoplasm (SMN) in patients with relapsed neuroblastoma after treatment with (131)I-MIBG suggest the possibility of increased risk. Incidence of and risk factors for SMN after (131)I-MIBG have not been defined. This is a multi-institutional retrospective review of patients with neuroblastoma treated with (131)I-MIBG therapy. A competing risk approach was used to calculate the cumulative incidence of SMN from time of first exposure to (131)I-MIBG. A competing risk regression was used to identify potential risk factors for SMN...
October 2016: European Journal of Cancer
Jiu Chen, Hao Shu, Zan Wang, Yafeng Zhan, Duan Liu, Wenxiang Liao, Lin Xu, Yong Liu, Zhijun Zhang
INTRODUCTION: Both remitted late-life depression (rLLD) and amnesiac mild cognitive impairment (aMCI) alter brain functions in specific regions of the brain. They are also disconnection syndromes that are associated with a high risk of developing Alzheimer's disease (AD). OBJECTIVES: Resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) was performed to define the shared and distinct aberrant patterns in intranetwork and internetwork connectivity between rLLD and aMCI and to determine how knowledge of these differences might contribute to our essential understanding of the altered sequences involved in functional systems both inside and outside of resting-state networks...
October 2016: Cortex; a Journal Devoted to the Study of the Nervous System and Behavior
Thomas Koed Doktor, Yimin Hua, Henriette Skovgaard Andersen, Sabrina Brøner, Ying Hsiu Liu, Anna Wieckowska, Maja Dembic, Gitte Hoffmann Bruun, Adrian R Krainer, Brage Storstein Andresen
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. SMN is expressed ubiquitously and functions in RNA processing pathways that include trafficking of mRNA and assembly of snRNP complexes. Importantly, SMA severity is correlated with decreased snRNP assembly activity. In particular, the minor spliceosomal snRNPs are affected, and some U12-dependent introns have been reported to be aberrantly spliced in patient cells and animal models...
August 23, 2016: Nucleic Acids Research
Mehdi Eshraghi, Emily McFall, Sabrina Gibeault, Rashmi Kothary
Spinal muscular atrophy (SMA) is caused by mutations or deletions in the Survival Motor Neuron 1 (SMN1) gene in humans. Modifiers of the SMA symptoms have been identified and genetic background has a substantial effect in the phenotype and survival of the severe mouse model of SMA. Previously, we generated the less severe Smn(2B/-) mice on a mixed genetic background. To assess the phenotype of Smn deficiency on a pure genetic background, we produced Smn(2B/2B) congenic mice on either the C57BL/6 (BL6) or FVB strain background and characterized them at the 6(th) generation by breeding to Smn(+/-) mice...
August 18, 2016: Human Molecular Genetics
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