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https://www.readbyqxmd.com/read/29790918/temporal-and-tissue-specific-variability-of-smn-protein-levels-in-mouse-models-of-spinal-muscular-atrophy
#1
Ewout Jn Groen, Elena Perenthaler, Natalie L Courtney, Crispin Y Jordan, Hannah K Shorrock, Dinja van der Hoorn, Yu-Ting Huang, Lyndsay M Murray, Gabriella Viero, Thomas H Gillingwater
Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by deleterious variants in SMN1 that lead to a marked decrease in survival motor neuron (SMN) protein expression. Humans have a second SMN gene (SMN2) that is almost identical to SMN1. However, due to alternative splicing the majority of SMN2 mRNA is translated into a truncated, unstable protein that is quickly degraded. Because the presence of SMN2 provides a unique opportunity for therapy development in SMA patients, the mechanisms that regulate SMN2 splicing and mRNA expression have been elucidated in great detail...
May 22, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29758563/pilot-study-of-population-based-newborn-screening-for-spinal-muscular-atrophy-in-new-york-state
#2
Jennifer N Kraszewski, Denise M Kay, Colleen F Stevens, Carrie Koval, Bianca Haser, Veronica Ortiz, Anthony Albertorio, Lilian L Cohen, Ritu Jain, Sarah P Andrew, Sally Dunaway Young, Nicole M LaMarca, Darryl C De Vivo, Michele Caggana, Wendy K Chung
PurposeTo determine feasibility and utility of newborn screening for spinal muscular atrophy (SMA) in New York State.MethodsWe validated a multiplex TaqMan real-time quantitative polymerase chain reaction assay using dried blood spots for SMA. From January 2016 to January 2017, we offered, consented, and screened 3,826 newborns at three hospitals in New York City and tested newborns for the deletion in exon 7 of SMN1.ResultsNinety-three percent of parents opted in for SMA screening. Overall the SMA carrier frequency was 1...
October 12, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29742241/therapeutic-advances-in-5q-linked-spinal-muscular-atrophy
#3
Umbertina Conti Reed, Edmar Zanoteli
Spinal muscular atrophy (SMA) is a severe and clinically-heterogeneous motor neuron disease caused, in most cases, by a homozygous mutation in the SMN1 gene. Regarding the age of onset and motor involvement, at least four distinct clinical phenotypes have been recognized. This clinical variability is, in part, related to the SMN2 copy number. By now, only supportive therapies have been available. However, promising specific therapies are currently being developed based on different mechanisms to increase the level of SMN protein; in particular, intrathecal antisense oligonucleotides that prevent the skipping of exon 7 during SMN2 transcription, and intravenous SMN1 insertion using viral vector...
April 2018: Arquivos de Neuro-psiquiatria
https://www.readbyqxmd.com/read/29703692/new-and-developing-therapies-in-spinal-muscular-atrophy
#4
REVIEW
Didu Kariyawasam, Kate A Carey, Kristi J Jones, Michelle A Farrar
Great progress has been made in the clinical translation of several therapeutic strategies for spinal muscular atrophy (SMA), including measures to selectively address Survival Motor Neuron (SMN) protein deficiency with SMN1 gene replacement or modulation of SMN2 encoded protein levels, as well as neuroprotective approaches and supporting muscle strength and function. This review highlights these novel therapies. This is particularly vital with the advent of the first disease modifying therapy, which has brought to the fore an array of questions surrounding who, how and when to treat, and stimulated challenges in resource limited healthcare systems to streamline access for those eligible for drug therapy...
April 5, 2018: Paediatric Respiratory Reviews
https://www.readbyqxmd.com/read/29672276/blocking-p62-sqstm1-dependent-smn-degradation-ameliorates-spinal-muscular-atrophy-disease-phenotypes
#5
Natalia Rodriguez-Muela, Andrey Parkhitko, Tobias Grass, Rebecca M Gibbs, Erika M Norabuena, Norbert Perrimon, Rajat Singh, Lee L Rubin
Spinal muscular atrophy (SMA), a degenerative motor neuron (MN) disease caused by loss of functional SMN protein due to SMN1 gene mutations, is a leading cause of infant mortality. Increasing SMN levels ameliorates the disease phenotype and is unanimously accepted as a therapeutic approach for SMA patients. The ubiquitin/proteasome system is known to regulate SMN protein levels; however whether autophagy controls SMN levels remains poorly explored. Here we show that SMN protein is degraded by autophagy. Pharmacological and genetic inhibition of autophagy increase SMN levels, while induction of autophagy decreases SMN...
April 19, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29656927/pontocerebellar-hypoplasia-type-1-for-the-neuropediatrician-genotype-phenotype-correlations-and-diagnostic-guidelines-based-on-new-cases-and-overview-of-the-literature
#6
I Ivanov, D Atkinson, I Litvinenko, L Angelova, S Andonova, H Mumdjiev, I Pacheva, M Panova, R Yordanova, V Belovejdov, A Petrova, M Bosheva, T Shmilev, A Savov, A Jordanova
Pontocerebellar hypoplasia type 1 (PCH1) is a major cause of non-5q spinal muscular atrophy (SMA). We screened 128 SMN1-negative SMA patients from Bulgaria for a frequent mutation -p.G31A in EXOSC3, and performed a literature review of all genetically verified PCH1 cases. Homozygous p.G31A/EXOSC3 mutation was identified in 14 Roma patients, representing three fourths of all our SMN1-negative Roma SMA cases. The phenotype of the p.G31A/EXOSC3 homozygotes was compared to the clinical presentation of all reported to date genetically verified PCH1 cases...
April 3, 2018: European Journal of Paediatric Neurology: EJPN
https://www.readbyqxmd.com/read/29649521/modelling-motor-neuron-disease-in-fruit-flies-lessons-from-spinal-muscular-atrophy
#7
Beppe Aquilina, Ruben J Cauchi
Motor neuron disease (MND) is characterised by muscle weakness and paralysis downstream of motor neuron degeneration. Genetic factors play a major role in disease pathogenesis and progression. This is best underscored by spinal muscular atrophy (SMA), the most common MND affecting children. Although SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene, partial compensation by the paralogous SMN2 gene and/or genetic modifiers influence age of onset and disease severity. SMA is also the first MND that is treatable thanks to the recent development of a molecular-based therapy...
April 9, 2018: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/29614695/treatment-algorithm-for-infants-diagnosed-with-spinal-muscular-atrophy-through-newborn-screening
#8
Jacqueline Glascock, Jacinda Sampson, Amanda Haidet-Phillips, Anne Connolly, Basil Darras, John Day, Richard Finkel, R Rodney Howell, Katherine Klinger, Nancy Kuntz, Thomas Prior, Perry B Shieh, Thomas Crawford, Doug Kerr, Jill Jarecki
BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of alpha motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron 1 gene (SMN1). In humans, a nearly identical copy gene, SMN2, is present. Because SMN2 has been shown to decrease disease severity in a dose-dependent manner, SMN2 copy number is predictive of disease severity. OBJECTIVE: To develop a treatment algorithm for SMA-positive infants identified through newborn screening based upon SMN2 copy number...
March 26, 2018: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/29598153/seamless-genetic-conversion-of-smn2-to-smn1-via-crispr-cpf1-and-single-stranded-oligodeoxynucleotides-in-spinal-muscular-atrophy-patient-specific-ipscs
#9
Miaojin Zhou, Zhiqing Hu, Liyan Qiu, Tao Zhou, Mai Feng, Qian Hu, Baitao Zeng, Zhuo Li, Qianru Sun, Yong Wu, Xionghao Liu, Lingqian Wu, Desheng Liang
Spinal muscular atrophy (SMA) is a kind of neuromuscular disease characterized by progressive motor neuron loss in the spinal cord. It is caused by mutations in the survival motor neuron 1 (SMN1) gene. SMN1 has a paralogous gene, survival motor neuron 2 (SMN2), in humans that is present in almost all SMA patients. The generation and genetic correction of SMA patient specific induced pluripotent stem cells (iPSCs) is a viable, autologous therapeutic strategy for the disease. Here, we generated c-Myc-free and non-integrating iPSCs from the urine cells of an SMA patient using an episomal iPSC reprogramming vector and designed a unique crRNA that does not have similar sequences (≤3 mismatches) anywhere in the human reference genome...
March 29, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29580671/intron-retained-transcripts-of-the-spinal-muscular-atrophy-genes-smn1-and-smn2
#10
Nur Imma Fatimah Harahap, Emma Tabe Eko Niba, Mawaddah Ar Rochmah, Yogik Onky Silvana Wijaya, Toshio Saito, Kayoko Saito, Hiroyuki Awano, Ichiro Morioka, Kazumoto Iijima, Poh San Lai, Masafumi Matsuo, Hisahide Nishio, Masakazu Shinohara
BACKGROUND: The SMN genes, SMN1 and SMN2, are highly homologous genes which are related to the development or clinical severity of spinal muscular atrophy. Some alternative splicing patterns of the SMN genes have been well documented. In 2007, an SMN1 transcript with a full sequence of intron 3 was reported as the first intron-retained SMN transcript. METHODS: Intron-retained SMN transcripts in various cells and tissues were studied using reverse transcription (RT)-PCR...
March 23, 2018: Brain & Development
https://www.readbyqxmd.com/read/29552580/plastin-3-promotes-motor-neuron-axonal-growth-and-extends-survival-in-a-mouse-model-of-spinal-muscular-atrophy
#11
Aziza Alrafiah, Evangelia Karyka, Ian Coldicott, Kayleigh Iremonger, Katherin E Lewis, Ke Ning, Mimoun Azzouz
Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease. SMA is caused by mutations in the survival motor neuron gene ( SMN1 ), leading to reduced levels of SMN protein in the CNS. The actin-binding protein plastin 3 (PLS3) has been reported as a modifier for SMA, making it a potential therapeutic target. Here, we show reduced levels of PLS3 protein in the brain and spinal cord of a mouse model of SMA. Our study also revealed that lentiviral-mediated PLS3 expression restored axonal length in cultured Smn-deficient motor neurons...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29504374/a-versatile-method-for-gene-dosage-quantification-multiplex-pcr-and-single-base-extension-for-copy-number-and-gene-conversion-identification-of-smn-genes
#12
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
https://www.readbyqxmd.com/read/29493298/phenotypic-and-genotypic-studies-of-als-cases-in-als-sma-families
#13
Philippe Corcia, Patrick Vourc'h, Helene Blasco, Philippe Couratier, Audrey Dangoumau, Remi Bellance, Claude Desnuelle, Fausto Viader, Vivien Pautot, Stephanie Millecamps, Salah Bakkouche, FranÇois Salachas, Christian R Andres, Vincent Meininger, William Camu
BACKGROUND: Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor neuron disorders in adulthood and infancy, respectively. There is a growing literature supporting common pathophysiological patterns between those disorders. One important clinical issue for that is the co-occurrence of both diseases within a family. OBJECTIVES: To collect families in which ALS and SMA patients co-exist and describe the phenotype and the genotype of ALS patients...
March 1, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/29478602/spinal-muscular-atrophy
#14
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
https://www.readbyqxmd.com/read/29462610/spinal-muscular-atrophy-selective-motor-neuron-loss-and-global-defect-in-the-assembly-of-ribonucleoproteins
#15
Christine E Beattie, Stephen J Kolb
Spinal muscular atrophy is caused by deletions or mutations in the SMN1 gene that result in reduced expression of the SMN protein. The SMN protein is an essential molecular chaperone that is required for the biogenesis of multiple ribonucleoprotein (RNP) complexes including spliceosomal small nuclear RNPs (snRNPs). Reductions in SMN expression result in a reduced abundance of snRNPs and to downstream RNA splicing alterations. SMN is also present in axons and dendrites and appears to have important roles in the formation of neuronal mRNA-protein complexes during development or neuronal repair...
February 17, 2018: Brain Research
https://www.readbyqxmd.com/read/29434670/advances-in-spinal-muscular-atrophy-therapeutics
#16
REVIEW
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
https://www.readbyqxmd.com/read/29434179/sma-diagnosis-detection-of-smn1-deletion-with-real-time-mcop-pcr-system-using-fresh-blood-dna
#17
Emma Tabe Eko Niba, Mawaddah Ar Rochmah, Nur Imma Fatimah Harahap, Hiroyuki Awano, Ichiro Morioka, Kazumoto Iijima, Toshio Saito, Kayoko Saito, Atsuko Takeuchi, Poh San Lai, Yoshihiro Bouike, Hisahide Nishio, Masakazu Shinohara
BACKGROUND: Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders. The symptoms are caused by defects of lower motor neurons in the spinal cord. More than 95% of SMA patients are homozygous for survival motor neuron 1 (SMN1) deletion. We previously developed a screening system for SMN1 deletion based on a modified competitive oligonucleotide priming-PCR (mCOP-PCR) technique using dried blood spot (DBS) on filter paper. This system is convenient for mass screening in the large population and/or first-tier diagnostic method of the patients in the remote areas...
December 18, 2017: Kobe Journal of Medical Sciences
https://www.readbyqxmd.com/read/29434173/gender-effects-on-the-clinical-phenotype-in-japanese-patients-with-spinal-muscular-atrophy
#18
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
https://www.readbyqxmd.com/read/29434172/new-improved-version-of-the-mcop-pcr-screening-system-for-detection-of-spinal-muscular-atrophy-gene-smn1-deletion
#19
Masakazu Shinohara, Mawaddah Ar Rochmah, Kenta Nakanishi, Nur Imma Fatimah Harahap, Emma Tabe Eko Niba, Toshio Saito, Kayoko Saito, Atsuko Takeuchi, Yoshihiro Bouike, Hisahide Nishio
BACKGROUND: Spinal muscular atrophy (SMA) is a frequent autosomal recessive disorder, characterized by lower motor neuron loss in the spinal cord. More than 95% of SMA patients show homozygous survival motor neuron 1 (SMN1) deletion. We previously developed a screening system for SMN1 deletion based on a modified competitive oligonucleotide priming-PCR (mCOP-PCR) technique. However, non-specific amplification products were observed with mCOP-PCR, which might lead to erroneous interpretation of the screening results...
September 7, 2017: Kobe Journal of Medical Sciences
https://www.readbyqxmd.com/read/29433793/correlation-between-sma-type-and-smn2-copy-number-revisited-an-analysis-of-625-unrelated-spanish-patients-and-a-compilation-of-2834-reported-cases
#20
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...
March 2018: Neuromuscular Disorders: NMD
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