共查询到20条相似文献,搜索用时 15 毫秒
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Jered V. McGivern Teresa N. Patitucci Joshua A. Nord Marie‐Elizabeth A. Barabas Cheryl L. Stucky Allison D. Ebert 《Glia》2013,61(9):1418-1428
Spinal muscular atrophy (SMA) is a genetic disorder caused by the deletion of the survival motor neuron 1 (SMN1) gene that leads to loss of motor neurons in the spinal cord. Although motor neurons are selectively lost during SMA pathology, selective replacement of SMN in motor neurons does not lead to full rescue in mouse models. Due to the ubiquitous expression of SMN, it is likely that other cell types besides motor neurons are affected by its disruption and therefore may contribute to disease pathology. Here we show that astrocytes in SMAΔ7 mouse spinal cord and from SMA‐induced pluripotent stem cells exhibit morphological and cellular changes indicative of activation before overt motor neuron loss. Furthermore, our in vitro studies show mis‐regulation of basal calcium and decreased response to adenosine triphosphate stimulation indicating abnormal astrocyte function. Together, for the first time, these data show early disruptions in astrocytes that may contribute to SMA disease pathology. 相似文献
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Qods Ymlahi-Ouazzani Odile J. Bronchain Elodie Paillard Chantal Ballagny Albert Chesneau Aurélie Jadaud André Mazabraud Nicolas Pollet 《Neurogenetics》2010,11(1):27-40
Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by motor neuron loss and skeletal muscle atrophy.
The loss of function of the smn1 gene, the main supplier of survival motor neuron protein (SMN) protein in human, leads to reduced levels of SMN and eventually
to SMA. Here, we ask if the amphibian Xenopus tropicalis can be a good model system to study SMA. Inhibition of the production of SMN using antisense morpholinos leads to caudal
muscular atrophy in tadpoles. Of note, early developmental patterning of muscles and motor neurons is unaffected in this system
as well as acetylcholine receptors clustering. Muscular atrophy seems to rather result from aberrant pathfinding and growth
arrest and/or shortening of motor axons. This event occurs in the absence of neuronal cell bodies apoptosis, a process comparable
to that of amyotrophic lateral sclerosis. Xenopus tropicalis is revealed as a complementary animal model for the study of SMA. 相似文献
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Gyu-Hwan Park Shingo Kariya Umrao R. Monani 《Current neurology and neuroscience reports》2010,10(2):108-117
Spinal muscular atrophy (SMA) is a common and often fatal neurodegenerative disease that primarily afflicts infants and young
children. SMA is caused by abnormally low levels of the survival motor neuron (SMN) protein resulting from a combination of
recessively inherited mutations in the SMN1 gene and the presence of an almost identical but partially functional copy gene, SMN2. Absence of the uniquely human SMN2 gene in SMA patients has never been reported because the SMN protein is indispensable for cell survival. Modeling SMA in
animals therefore poses a challenge. This review describes the different strategies used to overcome this hurdle and model
SMA in mice. We highlight new and emerging insights regarding SMA gained by studying the mice and illustrate how the animals
serve as important tools to understand and eventually treat the human disease. 相似文献
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Kesari A Misra UK Kalita J Mishra VN Pradhan S Patil SJ Phadke SR Mittal B 《Journal of neurology》2005,252(6):667-671
In view of the paucity of deletion studies of survival of motor neuron (SMN) and neuronal apoptosis inhibitor protein (NAIP) genes in Indian SMA patients, this study has been undertaken to determine the status of SMN1, SMN2 and NAIP gene deletions in Indian SMA patients. Clinically and neurophysiologically diagnosed SMA patients were included in the study. A gene deletion study was carried out in 45 proximal SMA patients and 50 controls of the same ethnic group. Both SMN1 and NAIP genes showed homozygous absence in 76 % and 31 % respectively in proximal SMA patients. It is proposed that the lower deletion frequency of SMN1 gene in Indian patients may be due to mutations present in other genes or population variation, which need further study. 相似文献
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Veldink JH van den Berg LH Cobben JM Stulp RP De Jong JM Vogels OJ Baas F Wokke JH Scheffer H 《Neurology》2001,56(6):749-752
BACKGROUND: Spinal muscular atrophy (SMA) results from mutations of the survival motor neuron (SMN) gene on chromosome 5. The SMN gene exists in two highly homologous copies, telomeric (SMN1) and centromeric (SMN2). SMA is caused by mutations in SMN1 but not SMN2. The clinical phenotype of SMA appears to be related to the expression of SMN2. Patients suffering from the milder forms of SMA carry more copies of the SMN2 gene compared with patients with more severe SMA. It is suggested that the SMN2 gene is translated into an at least partially functional protein that protects against loss of motor neurons. OBJECTIVE: To investigate whether genetic mechanisms implicated in motor neuron death in SMA have a role in ALS. METHODS: The presence of deletions of exons 7 and 8 of SMN1 and SMN2 was determined in 110 patients with sporadic ALS and compared with 100 unaffected controls. RESULTS: The presence of a homozygous SMN2 deletion was overrepresented in patients with ALS compared with controls (16% versus 4%; OR, 4.4; 95% CI, 1.4 to 13.5). Patients with a homozygous SMN2 deletion had a shorter median time of survival (p < 0.009). Furthermore, multivariate regression analysis showed that the presence of an SMN2 deletion was independently associated with survival time (p < 0.02). No homozygous deletions in SMN1 were found. Carrier status of SMA appeared to be equally present in patients and controls (1 in 20). CONCLUSION: These results indicate that, similar to SMA, the SMN2 gene can act as a prognostic factor and may therefore be a phenotypic modifier in sporadic ALS. Increasing the expression of the SMN2 gene may provide a strategy for treatment of motor neuron disease. 相似文献
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Scarciolla O Stuppia L De Angelis MV Murru S Palka C Giuliani R Pace M Di Muzio A Torrente I Morella A Grammatico P Giacanelli M Rosatelli MC Uncini A Dallapiccola B 《Neurogenetics》2006,7(4):269-276
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord, causing symmetric proximal muscle weakness. SMA is classified in three clinical types, SMA I, SMA II, and SMA III, based on the severity of the symptoms and the age of onset. About 95% of SMA cases are caused by homozygous deletion of the survival motor neuron 1 (SMN1) gene (5q13), or its conversion to SMN2. The molecular diagnosis of this disease is usually carried out by a polymerase chain reaction–restriction fragment length polymorphism approach able to evidence the absence of both SMN1 copies. However, this approach is not able to identify heterozygous healthy carriers, which show a very high frequency in general population (1:50). We used the multiple ligation-dependent probe amplification (MLPA) approach for the molecular diagnosis of SMA in 19 affected patient and in 57 individuals at risk to become healthy carriers. This analysis detected the absence of the homozygous SMN1 in all the investigated cases, and allowed to discriminate between SMN1 deletion and conversion to SMN2 on the basis of the size showed by the peaks specific for the different genes mapped within the SMA critical region. Moreover, MLPA analysis evidenced a condition of the absence of the heterozygous SMN1 in 33 out of the 57 relatives of the affected patients, demonstrating the usefulness of this approach in the identification of healthy carriers. Thus, the MLPA technique represents an easy, low cost, and high throughput system in the molecular diagnosis of SMA, both in affected patients and in healthy carriers. 相似文献
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Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder pathologically characterized by the degeneration of motor neurons in the spinal cord and muscle atrophy. Motor neuron loss often results in severe muscle weakness causing affected infants to die before reaching 2 years of age. Patients with milder forms of SMA exhibit slowly progressive muscle weakness over many years. SMA is caused by the loss of SMN1 and the retention of at least 1 copy of a highly homologous SMN2. An alternative splicing event in the pre-mRNA arising from SMN2 results in the production of low levels of functional SMN protein. To date, there are no effective treatments available to treat patients with SMA. However, over the last 2 decades, the development of SMA mouse models and the identification of therapeutic targets have resulted in a promising drug pipeline for SMA. Here, we highlight some of the therapeutic strategies that have been developed to activate SMN2 expression, modulate splicing of the SMN2 pre-mRNA, or replace SMN1 by gene therapy. After 2 decades of translational research, we now stand within reach of a treatment for SMA.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-015-0337-y) contains supplementary material, which is available to authorized users. 相似文献16.
El-Khodor BF Edgar N Chen A Winberg ML Joyce C Brunner D Suárez-Fariñas M Heyes MP 《Experimental neurology》2008,212(1):29-43
Spinal muscular atrophy (SMA) is characterized by selective loss of α-motor neurons and is caused by homozygous loss or mutation in the survival motor neuron (SMN1) gene. Loss of SMN1 is partially compensated by the copy gene, SMN2. Currently, there are no specific treatments for SMA. Key features of SMA are modeled in mice by deletion of murine Smn, and insertion of both full length human SMN2 gene and the major aberrant splice isoform of the SMN2 gene (SMNΔ7; [Le, T.T., Pham, L.T., Butchbach, M.E., Zhang, H.L., Monani, U.R., Coovert, D.D., Gavrilina, T.O., Xing, L., Bassell, G.J., and Burghes, A.H. 2005. SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 14: 845-857]). The present study identified moderate-throughput, quantitative behavioral tests in neonatal SMN2+/+;SMNΔ7+/+;Smn−/− mice. It also addresses methodological approaches and common interpretational challenges in a neonatal model with motor deficiencies and frequent deaths. Animals were assessed daily for body weight and survival, and every other day for neonatal well-being indices and tests of motor function such as performance on the hind-limb suspension test (a.k.a. tube test) and geotaxis. The tube test is a novel non-invasive motor function test specifically designed for neonatal rodents. We found progressive deterioration in SMA model mice for most measures studied particularly body weight, survival, body temperature and motor function with differences appearing as early as P3. Power analysis showed that body weight, survival, righting reflex, geotaxis and tube test had highest predictive power for drug efficacy studies. This multi-functional component battery of tests provides a rapid and efficient means to identify, evaluate and develop candidate therapies as a prelude to human clinical trials. 相似文献
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脊髓性肌萎缩症的快速基因诊断研究 总被引:2,自引:1,他引:1
目的研究我国近端型脊髓性肌萎缩症(SMA)患者的运动神经元生存基因(SMN)外显子的缺失情况,探讨其快速基因诊断的可行性和临床应用价值。方法应用PCR-酶切法检测26例确诊的SMA患者及20名正常对照SMN基因的第7、8号外显子的缺失情况。结果在26例及25例患者中,分别发现缺失了端粒SMN基因(SMN1)的第7和8号外显子,缺失率达100%(26/26)和96%(25/26),而正常对照及患者的家系成员均未发现外显子缺失。结论应用PCR-酶切法检测SMN1基因缺失从而进行SMA患者的基因诊断,具有准确、简便和快速的优点。 相似文献
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Ozgur Duman MD Hilmi Uysal MD Karen L. Skjei MD Ferah Kizilay MD Sibel Karauzum PhD Senay Haspolat MD 《Muscle & nerve》2013,48(1):117-121
Introduction: Generally, spinal muscular atrophy (SMA) is believed to be a pure motor neuron disease. We retrospectively evaluated our electrodiagnostic findings in SMA type 1 patients to demonstrate co‐existence of sensorimotor neuropathies. Methods: Electroneuromyographic (ENMG) studies in 15 patients (11 boys, 4 girls) were reviewed independently by 2 neurophysiologists. Upper extremity findings were compared with normal right arm controls. Results: Patient ages ranged from 1.5 to 26 months. Four SMA patients (26.7%) had decreased sensory nerve action potentials (SNAPs) or sensory nerve conduction velocities. Of them, median SNAPs could not be elicited in 3, and sural SNAPs could not be elicited in 2. Compound muscle action potential amplitudes were severely decreased in 14 (93.3%) and normal in 1. Conclusions: Survival motor neuron 1 (SMN1) gene analysis should be considered if clinical features are consistent with SMA, even if pathological or electrophysiological findings demonstrate peripheral sensorimotor polyneuropathies. Muscle Nerve, 2013 相似文献
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Bernal S Also-Rallo E Martínez-Hernández R Alías L Rodríguez-Alvarez FJ Millán JM Hernández-Chico C Baiget M Tizzano EF 《Neuromuscular disorders : NMD》2011,21(6):413-419
Spinal muscular atrophy (SMA) is caused by loss or mutations of the survival motor neuron 1 gene (SMN1). Its highly homologous copy, SMN2, is present in all SMA cases and is a phenotypic modifier. There are cases where asymptomatic siblings of typical SMA patients possess a homozygous deletion of SMN1 just like their symptomatic brothers or sisters. Plastin 3 (PLS3) when over expressed in lymphoblasts from females has been suggested to act as a genetic modifier of SMA.We studied PLS3 expression in four Spanish SMA families with discordant siblings haploidentical for the SMA locus. We excluded PLS3 as a possible modifier in two of our families with female discordant siblings. In the remaining two, we observed small differences in PLS3 expression between male and female discordant siblings. Indeed, we found that values of PLS3 expression in lymphoblasts and peripheral blood ranged from 12 to 200-fold less than those in fibroblasts. These findings warrant further investigation in motor neurons derived from induced pluripotential stem cells of these patients. 相似文献
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Eugenio Mercuri Giovanni Baranello Odile Boespflug-Tanguy Liesbeth De Waele Nathalie Goemans Janbernd Kirschner Riccardo Masson Elena S. Mazzone Astrid Pechmann Maria Carmela Pera Carole Vuillerot Silvia Bader-Weder Marianne Gerber Ksenija Gorni Janine Hoffart Heidemarie Kletzl Carmen Martin Tammy McIver Renata S. Scalco Wai Yin Yeung Laurent Servais SUNFISH Working Group 《European journal of neurology》2023,30(7):1945-1956