共查询到20条相似文献,搜索用时 93 毫秒
1.
I Miguel-Aliaga E Culetto D S Walker H A Baylis D B Sattelle K E Davies 《Human molecular genetics》1999,8(12):2133-2143
Spinal muscular atrophy (SMA) is a common disorder characterized by loss of lower motor neurones of the spinal cord. The disease is caused by mutations in the survival motor neurone ( SMN ) gene. SMN is ubiquitously expressed and evolutionarily conserved, and its role in RNA processing has been well established. However, these properties do not explain the observed specificity of motor neurone death. To gain further insight into the function of SMN, we have isolated and characterized the Caenorhabditis elegans orthologue of the SMN gene ( CeSMN ). Here we show that CeSMN is transmitted maternally as a predominantly nuclear factor, which remains present in all the blastomeres throughout embryonic development and onwards into adulthood. In adult nematodes, a CeSMN-green fluorescent protein fusion protein is expressed in a number of cell types including the germline. Both disruption of the endogenous CeSMN function and overexpression of the gene result in a severe decrease in the number of progeny and in locomotive defects. In addition, its transient knockdown leads to sterility caused by a defect in germ cell maturation. The expression pattern and functional properties so far observed for CeSMN, together with its unusual behaviour in the germline, indicate that SMN may be involved in specific gene expression events at these very early developmental stages. We have also identified a deletion in the CeSMN promoter region in egl-32. This mutant may become a useful genetic tool with which to explore regulation of CeSMN and hence provide possible clues for novel therapeutic strategies for SMA. 相似文献
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The distribution of SMN protein complex in human fetal tissues and its alteration in spinal muscular atrophy 总被引:1,自引:8,他引:1
Burlet P; Huber C; Bertrandy S; Ludosky MA; Zwaenepoel I; Clermont O; Roume J; Delezoide AL; Cartaud J; Munnich A; Lefebvre S 《Human molecular genetics》1998,7(12):1927-1933
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular
disorder characterized by degeneration of motor neurons of the spinal cord
and muscular atrophy. SMA is caused by alterations to the survival of motor
neuron (SMN) gene, the function of which has hitherto been unclear. Here,
we present immunoblot analyses showing that normal SMN protein expression
undergoes a marked decay in the postnatal period compared with fetal
development. Morphological and immunohistochemical analyses of the SMN
protein in human fetal tissues showed a general distribution in the
cytoplasm, except in muscle cells, where SMN protein was immunolocalized to
large cytoplasmic dot-like structures and was tightly associated with
membrane-free heavy sedimenting complexes. These cytoplasmic structures
were similar in size to gem. The SMN protein was markedly deficient in
tissues derived from type I SMA fetuses, including skeletal muscles and, as
previously shown, spinal cord. While our data do not help decide whether
SMA results from impaired SMN expression in spinal cord, skeletal muscle or
both, they suggest a requirement for SMN protein during embryo-fetal
development.
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Chan YB Miguel-Aliaga I Franks C Thomas N Trülzsch B Sattelle DB Davies KE van den Heuvel M 《Human molecular genetics》2003,12(12):1367-1376
Autosomal recessive spinal muscular atrophy (SMA) is linked to mutations in the survival motor neuron (SMN) gene. The SMN protein has been implicated at several levels of mRNA biogenesis and is expressed ubiquitously. Studies in various model organisms have shown that the loss of function of the SMN gene leads to embryonic lethality. The human contains two genes encoding for SMN protein and in patients one of these is disrupted. It is thought the remaining low levels of protein produced by the second SMN gene do not suffice and result in the observed specific loss of lower motor neurons and muscle wasting. The early lethality in the animal mutants has made it difficult to understand why primarily these tissues are affected. We have isolated a Drosophila smn mutant. The fly alleles contain point mutations in smn similar to those found in SMA patients. We find that zygotic smn mutant animals show abnormal motor behavior and that smn gene activity is required in both neurons and muscle to alleviate this phenotype. Physiological experiments on the fly smn mutants show that excitatory post-synaptic currents are reduced while synaptic motor neuron boutons are disorganized, indicating defects at the neuromuscular junction. Clustering of a neurotransmitter receptor subunit in the muscle at the neuromuscular junction is severely reduced. This new Drosophila model for SMA thus proposes a functional role for SMN at the neuromuscular junction in the generation of neuromuscular defects. 相似文献
5.
Wilfried Rossoll Ann-Kathrin Kr?ning Uta-Maria Ohndorf Clemens Steegborn Sibylle Jablonka Michael Sendtner 《Human molecular genetics》2002,11(1):93-105
Spinal muscular atrophy (SMA), the most common hereditary motor neuron disease in children and young adults is caused by mutations in the telomeric survival motor neuron (SMN1) gene. The human genome, in contrast to mouse, contains a second SMN gene (SMN2) which codes for a gene product which is alternatively spliced at the C-terminus, but also gives rise to low levels of full-length SMN protein. The reason why reduced levels of the ubiquitously expressed SMN protein lead to specific motor neuron degeneration without affecting other cell types is still not understood. Using yeast two-hybrid techniques, we identified hnRNP-R and the highly related gry-rbp/hnRNP-Q as novel SMN interaction partners. These proteins have previously been identified in the context of RNA processing, in particular mRNA editing, transport and splicing. hnRNP-R and gry-rbp/hnRNP-Q interact with wild-type Smn but not with truncated or mutant Smn forms identified in SMA. Both proteins are widely expressed and developmentally regulated with expression peaking at E19 in mouse spinal cord. hnRNP-R binds RNA through its RNA recognition motif domains. Interestingly, hnRNP-R is predominantly located in axons of motor neurons and co-localizes with Smn in this cellular compartment. Thus, this finding could provide a key to understand a motor neuron-specific Smn function in SMA. 相似文献
6.
Childhood onset spinal muscular atrophy (SMA) is a common autosomal recessive disorder primarily characterized by the loss of lower alpha motor neurons. The underlying chromosomal defects causing SMA have been found in the survival motor neuron (SMN) gene. SMN has been shown previously to play a role in both snRNP biogenesis and mRNA processing, although direct evidence for the relationship between SMN and disease pathology has not been elucidated. SMN orthologues have been isolated in many species including Caenorhabditis elegans and Danio rerio. To study the function of SMN, we have identified and characterized the Schizosaccharomyces pombe orthologue of human SMN, smn1 (+). We have demonstrated that smn1 (+) is essential for viability in S.pombe and yeast expressing missense mutations in Smn1p, which mimic mutations in patients with Type I SMA, show significant mislocalization of the protein and a decrease in cell viability. Wild-type Smn1p is localized predominantly in the nucleus whereas yeast expressing Smn1p with missense mutations or deletions of specific domains of the protein accumulate cytoplasmic aggregates. Overexpression of Smn1p results in an increase in the growth rate of cells. Furthermore, mutations within two highly conserved protein interaction domains have a dominant-negative effect on growth, indicating that each domain is of functional significance in S.pombe. These dominant phenotypes can be suppressed by overexpression of murine Smn in the same cell. Given the structural and functional similarities between the protein in fission yeast and higher eukaryotes, S.pombe will be an ideal organism to study the role of SMN in RNA processing. 相似文献
7.
Briese M Esmaeili B Fraboulet S Burt EC Christodoulou S Towers PR Davies KE Sattelle DB 《Human molecular genetics》2009,18(1):97-104
Spinal muscular atrophy is the most common genetic cause of infant mortality and is characterized by degeneration of lower motor neurons leading to muscle wasting. The causative gene has been identified as survival motor neuron (SMN). The invertebrate model organism Caenorhabditis elegans contains smn-1, the ortholog of human SMN. Caenorhabditis elegans smn-1 is expressed in various tissues including the nervous system and body wall muscle, and knockdown of smn-1 by RNA interference is embryonic lethal. Here we show that the smn-1(ok355) deletion, which removes most of smn-1 including the translation start site, produces a pleiotropic phenotype including late larval arrest, reduced lifespan, sterility as well as impaired locomotion and pharyngeal activity. Mutant nematodes develop to late larval stages due to maternal contribution of the smn-1 gene product that allows to study SMN-1 functions beyond embryogenesis. Neuronal, but not muscle-directed, expression of smn-1 partially rescues the smn-1(ok355) phenotype. Thus, the deletion mutant smn-1(ok355) provides a useful platform for functional analysis of an invertebrate ortholog of the human SMN protein. 相似文献
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Talbot K; Ponting CP; Theodosiou AM; Rodrigues NR; Surtees R; Mountford R; Davies KE 《Human molecular genetics》1997,6(3):497-500
The Survival Motor Neuron (SMN) gene shows deletions in the majority of
patients with Spinal Muscular Atrophy (SMA), a disease of motor neuron
degeneration. To date only two missense mutations have been reported in SMN
in patients with SMA. The fact that no SMN-homologues have been forthcoming
from data-base searching has resulted in a lack of hypotheses concerning
the structural and functional consequences of these mutations. Recently SMN
has been shown to interact with heterogeneous nuclear ribonucleoproteins
(hnRNPs) suggesting a role in mRNA metabolism. We describe a novel missense
mutation and the subsequent identification of a triplicated
tyrosine-glycine (Y-G) peptide sequence at the C-terminal of SMN which
encompasses each of the three predicted amino acid sequence substitutions.
We have identified apparent orthologues of SMN in Caenorhabditis elegans
and Schizosaccharomyces pombe. These sequences retain the highly conserved
Y-G motif and provide additional support for a role of SMN in mRNA
metabolism.
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10.
Vitte J Fassier C Tiziano FD Dalard C Soave S Roblot N Brahe C Saugier-Veber P Bonnefont JP Melki J 《The American journal of pathology》2007,171(4):1269-1280
Spinal muscular atrophy (SMA) is characterized by degeneration of lower motor neurons and caused by mutations of the SMN1 gene. SMN1 is duplicated in a homologous gene called SMN2, which remains present in patients. SMN has an essential role in RNA metabolism, but its role in SMA pathogenesis remains unknown. Previous studies suggested that in neurons the protein lacking the C terminus (SMN(Delta7)), the major product of the SMN2 gene, had a dominant-negative effect. We generated antibodies specific to SMN(FL) or SMN(Delta7). In transfected cells, the stability of the SMN(Delta7) protein was regulated in a cell-dependent manner. Importantly, whatever the human tissues examined, SMN(Delta7) protein was undetectable because of the instability of the protein, thus excluding a dominant effect of SMN(Delta7) in SMA. A similar decreased level of SMN(FL) was observed in brain and spinal cord samples from human SMA, suggesting that SMN(FL) may have specific targets in motor neurons. Moreover, these data indicate that the vulnerability of motor neurons cannot simply be ascribed to the differential expression or a more dramatic reduction of SMN(FL) in spinal cord when compared with brain tissue. Improving the stability of SMN(Delta7) protein might be envisaged as a new therapeutic strategy in SMA. 相似文献
11.
P Mohaghegh N R Rodrigues N Owen C P Ponting T T Le A H Burghes K E Davies 《European journal of human genetics : EJHG》1999,7(5):519-525
Autosomal recessive childhood onset spinal muscular atrophy (SMA) is a leading cause of infant mortality caused by mutations in the survival motor neuron (SMN) gene. The SMN protein is involved in RNA processing and is localised in structures called GEMs in the nucleus. Nothing is yet understood about why mutations in SMN gene result in the selective motor neuron loss observed in patients. The SMN protein domains conserved across several species may indicate functionally significant regions. Exon 3 of SMN contains homology to a tudor domain, where a Type I SMA patient has been reported to harbour a missense mutation. We have generated missense mutants in this region of SMN and have tested their ability to form GEMs when transfected into HeLa cells. Our results show such mutant SMN proteins still localise to GEMs. Furthermore, exon 7 deleted SMN protein appears to exert a dominant negative effect on localisation of endogenous SMN protein. However, exon 3 mutant protein and exon 5 deleted protein exert no such effect. 相似文献
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The role of histone acetylation in SMN gene expression 总被引:7,自引:0,他引:7
Kernochan LE Russo ML Woodling NS Huynh TN Avila AM Fischbeck KH Sumner CJ 《Human molecular genetics》2005,14(9):1171-1182
14.
Jarecki J Chen X Bernardino A Coovert DD Whitney M Burghes A Stack J Pollok BA 《Human molecular genetics》2005,14(14):2003-2018
We have exploited the existence of a second copy of the human SMN gene (SMN2) to develop a high-throughput screening strategy to identify potential small molecule therapeutics for the genetic disease spinal muscular atrophy (SMA), which is caused by the loss of the SMN1 gene. Our screening process was designed to identify synthetic compounds that increase the total amount of full-length SMN messenger RNA and protein arising from the SMN2 gene, thereby suppressing the deleterious effects of losing SMN1. A cell-based bioassay was generated that detects SMN2 promoter activity, on which greater than 550,000 compounds was tested. This resulted in the identification of 17 distinct compounds with confirmed biological activity on the cellular primary assay, belonging to nine different structural families. Six of the nine scaffolds were chosen on the basis of their drug-like features to be tested for their ability to modulate SMN gene expression in SMA patient-derived fibroblasts. Five of the six compound classes altered SMN mRNA levels or mRNA splicing patterns in SMA patient-derived fibroblasts. Two of the compound classes, a quinazoline compound series and an indole compound, also increased SMN protein levels and nuclear gem/Cajal body numbers in patient-derived cells. In addition, these two distinct scaffolds showed additive effects when used in combination, suggesting that they may act on different molecular targets. The work described here has provided the foundation for a successful medicinal chemistry effort to further advance these compounds as potential small molecule therapeutics for SMA. 相似文献
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Walker MP Rajendra TK Saieva L Fuentes JL Pellizzoni L Matera AG 《Human molecular genetics》2008,17(21):3399-3410
Spinal muscular atrophy (SMA) is a recessive neuromuscular disease caused by mutations in the human survival motor neuron 1 (SMN1) gene. The human SMN protein is part of a large macromolecular complex involved in the biogenesis of small ribonucleoproteins. Previously, we showed that SMN is a sarcomeric protein in flies and mice. In this report, we show that the entire mouse Smn complex localizes to the sarcomeric Z-disc. Smn colocalizes with alpha-actinin, a Z-disc marker protein, in both skeletal and cardiac myofibrils. Furthermore, this localization is both calcium- and calpain-dependent. Calpains are known to release proteins from various regions of the sarcomere as a part of the normal functioning of the muscle; however, this removal can be either direct or indirect. Using mammalian cell lysates, purified native SMN complexes, as well as recombinant SMN protein, we show that SMN is a direct target of calpain cleavage. Finally, myofibers from a mouse model of severe SMA, but not controls, display morphological defects that are consistent with a Z-disc deficiency. These results support the view that the SMN complex performs a muscle-specific function at the Z-discs. 相似文献
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Frameshift mutation in the survival motor neuron gene in a severe case of SMA type I 总被引:9,自引:9,他引:9
Brahe C; Clermont O; Zappata S; Tiziano F; Melki J; Neri G 《Human molecular genetics》1996,5(12):1971-1976
Recently, a spinal muscular atrophy (SMA) determining gene, termed survival
motor neuron (SMN) gene, has been isolated from the 5q13 region and found
deleted in most patients. A highly homologous copy of this gene has also
been isolated and located in a centromeric position. We have analyzed 158
patients (SMA types I-IV) and found deletions of SMN exon 7 in 96.8%.
Mutations other than gross deletions seem to be extremely rare. In one of
the undeleted SMA type I patients, a newborn who survived for only 42 days,
we detected a maternally inherited 5 bp microdeletion in exon 3, resulting
in a premature stop codon. By RT-PCR and long range PCR amplification we
were able to show that the deletion belongs to the SMN gene, rather than to
the centromeric copy, and that the proposita had no paternal SMN gene.
Analysis of the neuronal apoptosis inhibitor protein (NAIP) gene, which
maps close to SMN and has been proposed as a SMA modifying gene, suggests
the presence of at least one full-length copy. Haplotype analysis of
closely linked polymorphic markers suggests that the proposita also lacks
the maternally derived copy of the centromeric homologue of SMN supporting
the hypothesis that the severity of the phenotype might depend on the
reduced number of centromeric genes in addition to the frameshift mutation.
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