scholarly journals SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy

2015 ◽  
Vol 211 (1) ◽  
pp. 77-90 ◽  
Author(s):  
Vittoria Pagliarini ◽  
Laura Pelosi ◽  
Maria Blaire Bustamante ◽  
Annalisa Nobili ◽  
Maria Grazia Berardinelli ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Messenger Rna ◽  
Muscular Atrophy ◽  
Splicing Factors ◽  
Hnrnp A1 ◽  
Smn1 Gene ◽  
Smn2 Gene ◽  
Physiological Regulator

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of motor neurons in patients with null mutations in the SMN1 gene. The almost identical SMN2 gene is unable to compensate for this deficiency because of the skipping of exon 7 during pre–messenger RNA (mRNA) processing. Although several splicing factors can modulate SMN2 splicing in vitro, the physiological regulators of this disease-causing event are unknown. We found that knockout of the splicing factor SAM68 partially rescued body weight and viability of SMAΔ7 mice. Ablation of SAM68 function promoted SMN2 splicing and expression in SMAΔ7 mice, correlating with amelioration of SMA-related defects in motor neurons and skeletal muscles. Mechanistically, SAM68 binds to SMN2 pre-mRNA, favoring recruitment of the splicing repressor hnRNP A1 and interfering with that of U2AF65 at the 3′ splice site of exon 7. These findings identify SAM68 as the first physiological regulator of SMN2 splicing in an SMA mouse model.

scholarly journals AN AYURVEDIC MANAGEMENT OF SPINAL MUSCULAR ATROPHY (SMA) – A CASE STUDY

2021 ◽  
Vol 9 (11) ◽  
pp. 2897-2902
Author(s):  
Raheena B ◽  
Shaila Borannavar ◽  
Ananta S Desai
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Autosomal Recessive ◽  
Muscular Atrophy ◽  
Genetic Disorder ◽  
The Body ◽  
Erect Posture ◽  
Smn1 Gene ◽  
Autosomal Recessive Pattern

Spinal Muscular Atrophy (SMA) is the second leading genetic disorder inherited in the autosomal recessive pattern due to the absence of the SMN1 gene characterized by loss of motor neurons and progressive muscle wasting, often leading to dependent life and decreased life span. In Ayurveda, this condition can be considered as Kulaja Vyadhi wherein the patient’s Mamsa and Snayu is affected by Vata. This can be regarded as Mamsa-Snayugata Sarvanga Vata. It is said that Prakruta Vata dosha is the life, it is the strength, it is the sustainer of the body, it holds the body and life together. If it is Vikruta it produces Sankocha, Khanja, Kubjatva, Pangutva, Khalli and Soshana of Anga. So, in this disease aggravated Vata does the vitiation of Mamsa and Snayu thus leading to Soshana of both, resulting in Stambha, Nischalikarana of Avayava. A 21years female patient was admitted to our I.P.D with c/o of reduced strength in all four limbs leading to the inability to walk and to maintain erect posture during standing and sitting positions. Based on Ayurvedic principles the patient was initially subjected to Avaranahara Chikitsa followed by Brimhana line of management. Keywords: Mamsagata vata, Snayugata vata, Sarvanga vata, Spinal muscular atrophy (SMA)

scholarly journals Clinical features and genetics in non-5q spinal muscular atrophy caused by acid ceramidase deficiency

2021 ◽  
Vol 14 (3) ◽  
pp. 424-428
Author(s):  
Mihaela Axente ◽  
◽  
◽  
Elena-Silvia Shelby ◽  
Andrada Mirea ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Smn1 Gene ◽  
Progressive Degeneration ◽  
Whole Exome ◽  
Uncertain Significance ◽  
Progressive Myoclonic Epilepsy ◽  
Ceramidase Deficiency ◽  
Next Generation Sequencing Ngs

Spinal muscular atrophy (SMA) is a spectrum of genetically and clinically heterogeneous diseases leading to the progressive degeneration of peripheric motor neurons with subsequent muscle weakness and atrophy. More than 95% of the cases of SMA are represented by homozygous mutations of the SMN1 gene (5q-SMA). Because this disease represents the leading cause of death due to a genetic cause and due to the availability of genetic therapies which can now save the life of the patient and stop the progress of the disease, early diagnosis is crucial. This report presents the case of a 13-year-old patient admitted to our hospital in 2018 who presented a phenotype typical to 5q-SMA. Next-generation sequencing (NGS) and Sanger sequencing of the SMN1 gene were performed, and a negative result was obtained. Consequently, we continued testing using whole-exome sequencing and discovered three mutations in the ASAH1 gene (one pathogenic and two variants of uncertain significance). Pathogenic mutations in the ASAH1 gene are responsible for spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and Farber disease, which overlapped with our patient’s phenotype. Currently, there are 45 SMA cases caused by mutations in the ASAH1 gene reported worldwide; however, the present case is the first reported in Romania.

scholarly journals A Drosophila melanogaster model of spinal muscular atrophy reveals a function for SMN in striated muscle

2007 ◽  
Vol 176 (6) ◽  
pp. 831-841 ◽  
Author(s):  
T.K. Rajendra ◽  
Graydon B. Gonsalvez ◽  
Michael P. Walker ◽  
Karl B. Shpargel ◽  
Helen K. Salz ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Striated Muscle ◽  
Flight Muscle ◽  
Muscular Atrophy ◽  
Survival Motor Neurons ◽  
Protein Levels

Mutations in human survival motor neurons 1 (SMN1) cause spinal muscular atrophy (SMA) and are associated with defects in assembly of small nuclear ribonucleoproteins (snRNPs) in vitro. However, the etiological link between snRNPs and SMA is unclear. We have developed a Drosophila melanogaster system to model SMA in vivo. Larval-lethal Smn-null mutations show no detectable snRNP reduction, making it unlikely that these animals die from global snRNP deprivation. Hypomorphic mutations in Smn reduce dSMN protein levels in the adult thorax, causing flightlessness and acute muscular atrophy. Mutant flight muscle motoneurons display pronounced axon routing and arborization defects. Moreover, Smn mutant myofibers fail to form thin filaments and phenocopy null mutations in Act88F, which is the flight muscle–specific actin isoform. In wild-type muscles, dSMN colocalizes with sarcomeric actin and forms a complex with α-actinin, the thin filament crosslinker. The sarcomeric localization of Smn is conserved in mouse myofibrils. These observations suggest a muscle-specific function for SMN and underline the importance of this tissue in modulating SMA severity.

scholarly journals Electrophysiological Properties of Motor Neurons in a Mouse Model of Severe Spinal Muscular Atrophy: In Vitro versus In Vivo Development

PLoS ONE ◽  
2010 ◽  
Vol 5 (7) ◽  
pp. e11696 ◽  
Author(s):  
Hongmei Zhang ◽  
Natallia Robinson ◽  
Chiayen Wu ◽  
Wenlan Wang ◽  
Melissa A. Harrington
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Electrophysiological Properties

scholarly journals Phenotype modifiers of spinal muscular atrophy: the number of SMN2 gene copies, deletion in the NAIP gene and probably gender influence the course of the disease.

2009 ◽  
Vol 56 (1) ◽  
Author(s):  
Maria Jedrzejowska ◽  
Michał Milewski ◽  
Janusz Zimowski ◽  
Janina Borkowska ◽  
Anna Kostera-Pruszczyk ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Autosomal Recessive ◽  
Clinical Symptoms ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Smn1 Gene ◽  
Gender Influence ◽  
Gene Copies ◽  
Smn2 Gene ◽  
Naip Gene

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene. It is characterized by significant phenotype variability. In this study, we analyzed possible phenotype modifiers of the disease - the size of the deletion in the SMA region, the number of SMN2 gene copies, as well as the effect of gender. Among the factors analyzed, two seem to influence the SMA phenotype: the number of SMN2 gene copies and a deletion in the NAIP gene. A higher number of SMN2 copies makes the clinical symptoms more benign, and the NAIP gene deletion is associated with a more severe phenotype. The influence of gender remains unclear. In a group of 1039 patients, 55% of whom were male, the greatest disproportion was in the SMA1 (F/M = 0.78) and SMA3b (F/M = 0.45) forms. In SMA1 a deletion in the NAIP gene was seen twice as frequently in girls compared to boys. In three patients, we observed genotypes atypical for the chronic forms of SMA: two patients with SMA3a and 3b had a deletion of the NAIP gene, and a third patient with SMA2 had one copy of the SMN2 gene.

scholarly journals Case Study on Ayurvedic Management of Spinal Muscular Atrophy (SMA)

2018 ◽  
Vol 9 (3) ◽  
pp. 225-230
Author(s):  
Krishna Santoshi M ◽  
Krishnaiah N
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Genetic Disorder ◽  
The Body ◽  
Treatment Modalities ◽  
Smn1 Gene ◽  
Hands And Feet ◽  
Autosomal Recessive Pattern

Spinal Muscular Atrophy (SMA) is the second leading genetic disorder inherited in autosomal recessive pattern due to absence of SMN1 gene characterized by loss of motor neurons and progressive muscle wasting, often leading to dependent life and decreased life span. In Ayurveda, SMA can be considered as a type of janma jaata Vata vikara as it has been mentioned that: “Tatra va gati gandhanayoriti vata” that means all the movements of the body are controlled by vata. In Vata vyadhi Lakshanas, few symptoms like Anganam sosha (Atrophy or emaciation of limbs), Sankocha (Contraction), Kanja, Pangulya, Kubjatva (Lameness of hands and feet, hunch-back and shortness), are considered, few of which are also observed in the Spinal Muscular Atrophy. A 2yrs female patient was admitted in our I.P.D who was a known case of SMA II presented with complaints of inability in sitting for longer time without support, unable to stand and walk even with support. Through Ayurvedic principles we have treated adopting various vata hara treatment modalities & also with few palliative treatments as per the need in view of enhancing the quality living.  

scholarly journals A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy

2003 ◽  
Vol 160 (1) ◽  
pp. 41-52 ◽  
Author(s):  
Umrao R. Monani ◽  
Matthew T. Pastore ◽  
Tatiana O. Gavrilina ◽  
Sibylle Jablonka ◽  
Thanh T. Le ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Autosomal Recessive Disorder ◽  
Type I ◽  
Missense Mutations ◽  
Smn2 Gene ◽  
Smn Gene

5q spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and the leading genetic cause of infantile death. Patients lack a functional survival of motor neurons (SMN1) gene, but carry one or more copies of the highly homologous SMN2 gene. A homozygous knockout of the single murine Smn gene is embryonic lethal. Here we report that in the absence of the SMN2 gene, a mutant SMN A2G transgene is unable to rescue the embryonic lethality. In its presence, the A2G transgene delays the onset of motor neuron loss, resulting in mice with mild SMA. We suggest that only in the presence of low levels of full-length SMN is the A2G transgene able to form partially functional higher order SMN complexes essential for its functions. Mild SMA mice exhibit motor neuron degeneration, muscle atrophy, and abnormal EMGs. Animals homozygous for the mutant transgene are less severely affected than heterozygotes. This demonstrates the importance of SMN levels in SMA even if the protein is expressed from a mutant allele. Our mild SMA mice will be useful in (a) determining the effect of missense mutations in vivo and in motor neurons and (b) testing potential therapies in SMA.

scholarly journals Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development

2021 ◽  
Vol 22 (15) ◽  
pp. 7896
Author(s):  
Matthew E. R. Butchbach
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Smn1 Gene ◽  
Spinal Motor Neurons ◽  
Copy Numbers ◽  
Smn Protein ◽  
High Degree

Spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide that is characterized by loss of spinal motor neurons leading to muscle weakness and atrophy. SMA results from the loss of survival motor neuron 1 (SMN1) gene but retention of its paralog SMN2. The copy numbers of SMN1 and SMN2 are variable within the human population with SMN2 copy number inversely correlating with SMA severity. Current therapeutic options for SMA focus on increasing SMN2 expression and alternative splicing so as to increase the amount of SMN protein. Recent work has demonstrated that not all SMN2, or SMN1, genes are equivalent and there is a high degree of genomic heterogeneity with respect to the SMN genes. Because SMA is now an actionable disease with SMN2 being the primary target, it is imperative to have a comprehensive understanding of this genomic heterogeneity with respect to hybrid SMN1–SMN2 genes generated by gene conversion events as well as partial deletions of the SMN genes. This review will describe this genetic heterogeneity in SMA and its impact on disease phenotype as well as therapeutic efficacy.

scholarly journals NOVA1 Promotes SMN2 Exon 7 Splicing via Binding the UCAC Motif and Increases SMN Protein Expression

2021 ◽  
Author(s):  
Lili Du ◽  
Junjie Sun ◽  
Zhiheng Chen ◽  
Yixiang Shao ◽  
Liucheng Wu
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Splicing Factors ◽  
Nissl Staining ◽  
Homologous Genes ◽  
Pathogenic Factors ◽  
Neural Tissues ◽  
Inclusion Rate ◽  
Smn Protein

Abstract Spinal muscular atrophy (SMA) is a rare hereditary neuromuscular disease with high lethality rate in infants. Homologous genes SMN1 and SMN2 were reported to be SMA pathogenic factors. Studies showed that high inclusion of SMN2 exon 7 increased SMN expression which in turn ameliorated the severity of SMA. The inclusion rate of SMN2 exon 7 was higher in neural tissues than that in non-neural tissues. Expression of splicing factors that regulate inclusion of SMN2 exon 7 were significantly increased in neural tissues compared to non-neural ones. A positive correlation was checked between expression of neuro-oncological ventral antigen 1(NOVA1) and SMN in central nervous system. In addition, reduced number of neurons in the spinal cord anterior horn was determined by Nissl staining in SMA mice from postnatal day 1 to 7 continuously. Meanwhile, NOVA1 was presented in motor neurons and gradually decreased as SMA ongoing. Moreover, SMN2 exon 7 inclusion and protein level were enhanced by overexpressing NOVA1, while the enhancement was reversed when NOVA1 knockdown in vitro. Finally, the “YCAY” motif (Y is pyrimidine, U or C) was located in the exon 7 of SMN2 and was critical for NOVA1 binding and promoting the inclusion of exon 7. Mutagenesis experiments revealed that CA was essential for the exon 7 inclusion while less influence was detected by changing order of Y in the motif. Collectively, NOVA1 interacted with “YCAY” motif in exon 7 of SMN2 and thus enhanced the inclusion of exon 7 in SMN2 which in turn increased the level of SMN protein. Our data may provide new insights into the treatment of SMA disease.

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