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https://www.readbyqxmd.com/read/27917293/alternative-splicing-of-a-cryptic-exon-embedded-in-intron-6-of-smn1-and-smn2
#1
Satomi Yoshimoto, Nur Imma Fatimah Harahap, Yuko Hamamura, Mawaddah Ar Rochmah, Ai Shima, Naoya Morisada, Masakazu Shinohara, Toshio Saito, Kayoko Saito, Poh San Lai, Masafumi Matsuo, Hiroyuki Awano, Ichiro Morioka, Kazumoto Iijima, Hisahide Nishio
Both survival of motor neuron (SMN) genes are associated with spinal muscular atrophy; mutations in SMN1 cause the disease, and SMN2 modulates its severity. It is established that different alternative splicing of exon 7 occurs for SMN1 and SMN2, and a cryptic exon was recently found in intron 6 of both genes. Here, we characterize this cryptic exon and clarify its alternative splicing pattern in control and spinal muscular atrophy cells.
2016: Human Genome Variation
https://www.readbyqxmd.com/read/27911332/type-0-spinal-muscular-atrophy-further%C3%A2-delineation-of-prenatal-and%C3%A2-postnatal-features-in-16-patients
#2
Sarah Grotto, Jean-Marie Cuisset, Stéphane Marret, Séverine Drunat, Patricia Faure, Séverine Audebert-Bellanger, Isabelle Desguerre, Vincent Flurin, Anne-Gaëlle Grebille, Anne-Marie Guerrot, Hubert Journel, Gilles Morin, Ghislaine Plessis, Sylvain Renolleau, Joëlle Roume, Brigitte Simon-Bouy, Renaud Touraine, Marjolaine Willems, Thierry Frébourg, Eric Verspyck, Pascale Saugier-Veber
BACKGROUND: Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. OBJECTIVE: The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. METHODS: SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database...
November 29, 2016: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/27907179/correction-cervical-spinal-cord-atrophy-profile-in-adult-smn1-linked-sma
#3
Mohamed-Mounir El Mendili, Timothée Lenglet, Tanya Stojkovic, Anthony Behin, Raquel Guimarães-Costa, François Salachas, Vincent Meininger, Gaelle Bruneteau, Nadine Le Forestier, Pascal Laforêt, Stéphane Lehéricy, Habib Benali, Pierre-François Pradat
[This corrects the article DOI: 10.1371/journal.pone.0152439.].
2016: PloS One
https://www.readbyqxmd.com/read/27907033/normalization-of-patient-identified-plasma-biomarkers-in-smn%C3%AE-7-mice-following-postnatal-smn-restoration
#4
W David Arnold, Sandra Duque, Chitra C Iyer, Phillip Zaworski, Vicki L McGovern, Shannon J Taylor, Katharine M von Herrmann, Dione T Kobayashi, Karen S Chen, Stephen J Kolb, Sergey V Paushkin, Arthur H M Burghes
INTRODUCTION AND OBJECTIVE: Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. SMA is caused by homozygous loss of the SMN1 gene and retention of the SMN2 gene resulting in reduced levels of full length SMN protein that are insufficient for motor neuron function. Various treatments that restore levels of SMN are currently in clinical trials and biomarkers are needed to determine the response to treatment. Here, we sought to investigate in SMA mice a set of plasma analytes, previously identified in patients with SMA to correlate with motor function...
2016: PloS One
https://www.readbyqxmd.com/read/27894243/spinal-muscular-atrophy-more-than-a-disease-of-motor-neurons
#5
L A Nash, J K Burns, J W Chardon, R Kothary, R J Parks
Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- motor neurons, leading to their degeneration and subsequent atrophy of limb and trunk muscles, progressing to death in severe forms of the disease. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e...
November 28, 2016: Current Molecular Medicine
https://www.readbyqxmd.com/read/27893852/a-comparative-study-of-smn-protein-and-mrna-in-blood-and-fibroblasts-in-patients-with-spinal-muscular-atrophy-and-healthy-controls
#6
Renske I Wadman, Marloes Stam, Marc D Jansen, Yana van der Weegen, Camiel A Wijngaarde, Oliver Harschnitz, Peter Sodaar, Kees P J Braun, Dennis Dooijes, Henny H Lemmink, Leonard H van den Berg, W Ludo van der Pol
BACKGROUND: Clinical trials to test safety and efficacy of drugs for patients with spinal muscular atrophy (SMA) are currently underway. Biomarkers that document treatment-induced effects are needed because disease progression in childhood forms of SMA is slow and clinical outcome measures may lack sensitivity to detect meaningful changes in motor function in the period of 1-2 years of follow-up during randomized clinical trials. OBJECTIVE: To determine and compare SMN protein and mRNA levels in two cell types (i...
2016: PloS One
https://www.readbyqxmd.com/read/27891608/compensatory-axon-sprouting-for-very-slow-axonal-die-back-in-a-transgenic-model-of-spinal-muscular-atrophy-type-iii
#7
Esther Udina, Charles Putman, Luke Harris, N Tyreman, Victoria Cook, Tessa Gordon
Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and is the leading genetic cause of infantile death. Patients lack the SMN1 gene with the severity of the disease depending on the number of copies of the highly homologous SMN2 gene. Although motoneuron death in the Smn+/- transgenic mouse model of mildest form of SMA, SMA type III, has been reported, we have used retrograde tracing of sciatic and femoral motoneurons in the hindlimb with recording of muscle and motor unit isometric forces to count the number of motoneurons with intact neuromuscular connections...
November 28, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27843464/molecular-genetic-analysis-of-survival-motor-neuron-gene-in-460-turkish-cases-with-suspicious-spinal-muscular-atrophy-disease
#8
Afrooz Rashnonejad, Huseyin Onay, Tahir Atik, Ozlem Atan Sahin, Sarenur Gokben, Hasan Tekgul, Ferda Ozkinay
OBJECTIVE: To describe 12 yr experience of molecular genetic diagnosis of Spinal Muscular Atrophy (SMA) in 460 cases of Turkish patients. MATERIALS & METHODS: A retrospective analysis was performed on data from 460 cases, referred to Medical Genetics Laboratory, Ege University's Hospital, Izmir, Turkey, prediagnosed as SMA or with family history of SMA between 2003 and 2014. The PCR-restriction fragment length polymorphism (RFLP) and the Multiplex ligation-dependent probe amplification (MLPA) analysis were performed to detect the survival motor neuron (SMN)1 deletions and to estimate SMN1 and SMN2 gene copy numbers...
2016: Iranian Journal of Child Neurology
https://www.readbyqxmd.com/read/27807335/-clinical-features-of-a-genetically-identified-spinal-and-%C3%A2-bulbar-muscular-atrophy-pedigree
#9
Zhe Wang, Qihua Chen, Qiuxiang Li, Fangfang Bi
Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked motor neuron disease with significant phenotypic viability. Here, we present a genetically identified SBMA family without bulbar paralysis or androgen insensitivity. All four male patients presented with progressive lower motor neuron paralysis in all limbs, with distal extremities more dominant. None of them had bulbar palsy or androgen insensitivity. A consistently mild elevated blood creatine phosphokinase (CPK) levels were detected in all patients and the EMG showed a chronic neurogenic damage...
October 28, 2016: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
https://www.readbyqxmd.com/read/27754957/evaluation-and-comparison-of-three-assays-for-molecular-detection-of-spinal-muscular-atrophy
#10
Liang Li, Wan-Jun Zhou, Ping Fang, Ze-Yan Zhong, Jian-Sheng Xie, Ti-Zhen Yan, Jian Zeng, Xu-Hui Tan, Xiang-Min Xu
BACKGROUND: Spinal muscular atrophy (SMA) is mainly caused by deletions in SMA-related genes. The objective of this study was to develop gene-dosage assays for diagnosing SMA. METHODS: A multiplex, quantitative PCR assay and a CNVplex assay were developed for determining the copy number of SMN1, SMN2, and NAIP. Reproducibility and specificity of the two assays were compared to a multiple ligation-dependent probe amplification (MLPA) assay. To evaluate reproducibility, 30 samples were analyzed three times using the three assays...
October 18, 2016: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/27730768/genotype-phenotype-correlation-of-smn1-and-naip-deletions-in-korean-patients-with-spinal-muscular-atrophy
#11
Eun Ji Ahn, Mi Sun Yum, Eun Hee Kim, Han Wook Yoo, Beom Hee Lee, Gu Hwan Kim, Tae Sung Ko
BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. Most SMA patients have a homozygous deletion in survival of motor neuron 1 (SMN1) gene, and neuronal apoptosis inhibitory protein (NAIP) gene is considered a phenotype modifier. We investigated the genotype-phenotype correlation of SMN1 and NAIP deletions in Korean SMA patients. METHODS: Thirty-three patients (12 males and 21 females) treated at the Asan Medical Center between 1999 and 2013 were analyzed retrospectively...
October 7, 2016: Journal of Clinical Neurology
https://www.readbyqxmd.com/read/27698380/survival-motor-neuron-smn-protein-is-required-for-normal-mouse-liver-development
#12
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
https://www.readbyqxmd.com/read/27652289/efficacy-and-biodistribution-analysis-of-intracerebroventricular-administration-of-an-optimized-scaav9-smn1-vector-in-a-mouse-model-of-spinal-muscular-atrophy
#13
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
https://www.readbyqxmd.com/read/27648268/co-segregation-of-a-homozygous-smn1-deletion-and-a-heterozygous-pmp22-duplication-in-a-patient
#14
Raquel M Fernández, Ana Peciña, Beatriz Muñoz-Cabello, Guillermo Antiñolo, Salud Borrego
Despite co-segregation of two different genetic neurological disorders within a family is rare, clinicians should take into consideration this possibility in patients presenting with unusual complex phenotypes or with unexpected electrophysiological findings. Here, we report a Spanish 11-month-old patient with spinal muscular atrophy type 2 and Charcot-Marie-Tooth 1A.
September 2016: Clinical Case Reports
https://www.readbyqxmd.com/read/27621445/systemic-peptide-mediated-oligonucleotide-therapy-improves-long-term-survival-in-spinal-muscular-atrophy
#15
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
https://www.readbyqxmd.com/read/27577871/synaptotagmin-2-and-1-linked-to-neurotransmission-impairment-and-vulnerability-in-spinal-muscular-atrophy
#16
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
https://www.readbyqxmd.com/read/27577201/-application-of-droplet-digital-pcr-technology-for-genetic-testing-and-prenatal-diagnosis-of-spinal-muscular-atrophy
#17
Yang Zou, Peiwen Xu, Jie Li, Sexin Huang, Ming Gao, Ranran Kang, Xuan Gao, Yuan Gao
OBJECTIVE: To explore the clinical application of droplet digital PCR (ddPCR) for genetic testing and prenatal diagnosis of spinal muscular atrophy (SMA) with deletion of SMN1 gene exon 7. METHODS: A total of 138 clinical samples, including 121 peripheral blood, 13 amniotic fluid, 2 umbilical cord blood and 2 chorionic villi from 56 SMA families, were tested by both ddPCR and multiplex ligation-dependent probe amplification (MLPA). Results of the two approaches were analyzed with commercial software QuantaSoft (ddPCR) and Coffalyser (MLPA), respectively...
October 2016: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/27538421/effect-of-genetic-background-on-the-phenotype-of-the-smn2b-mouse-model-of-spinal-muscular-atrophy
#18
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
https://www.readbyqxmd.com/read/27510309/genotype-phenotype-correlation-of-smn-locus-genes-in-spinal-muscular-atrophy-children-from-argentina
#19
Sofía Medrano, Soledad Monges, Luis Pablo Gravina, Laura Alías, Julieta Mozzoni, Hilda Verónica Aráoz, Sara Bernal, Angélica Moresco, Lilien Chertkoff, Eduardo Tizzano
BACKGROUND/PURPOSE: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, considered one of the leading causes of infant mortality. It is caused by mutations in the SMN1 gene. A highly homologous copy of this gene named SMN2 and other neighbouring genes, SERF1A and NAIP, are considered phenotypic modifiers of the disease. In recent years, notable advances have been made in SMA research regarding evaluation, prognosis, and therapeutic options. Thus, genotype-phenotype studies in SMA are important to stratify patients for motor function tests and for envisaged clinical trials...
December 0: European Journal of Paediatric Neurology: EJPN
https://www.readbyqxmd.com/read/27499521/the-power-of-human-protective-modifiers-pls3-and-coro1c-unravel-impaired-endocytosis-in-spinal-muscular-atrophy-and-rescue-sma-phenotype
#20
Seyyedmohsen Hosseinibarkooie, Miriam Peters, Laura Torres-Benito, Raphael H Rastetter, Kristina Hupperich, Andrea Hoffmann, Natalia Mendoza-Ferreira, Anna Kaczmarek, Eva Janzen, Janine Milbradt, Tobias Lamkemeyer, Frank Rigo, C Frank Bennett, Christoph Guschlbauer, Ansgar Büschges, Matthias Hammerschmidt, Markus Riessland, Min Jeong Kye, Christoph S Clemen, Brunhilde Wirth
Homozygous loss of SMN1 causes spinal muscular atrophy (SMA), the most common and devastating childhood genetic motor-neuron disease. The copy gene SMN2 produces only ∼10% functional SMN protein, insufficient to counteract development of SMA. In contrast, the human genetic modifier plastin 3 (PLS3), an actin-binding and -bundling protein, fully protects against SMA in SMN1-deleted individuals carrying 3-4 SMN2 copies. Here, we demonstrate that the combinatorial effect of suboptimal SMN antisense oligonucleotide treatment and PLS3 overexpression-a situation resembling the human condition in asymptomatic SMN1-deleted individuals-rescues survival (from 14 to >250 days) and motoric abilities in a severe SMA mouse model...
September 1, 2016: American Journal of Human Genetics
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