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1.
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
2.
Young PJ Man NT Lorson CL Le TT Androphy EJ Burghes AH Morris GE 《Human molecular genetics》2000,9(19):2869-2877
Spinal muscular atrophy (SMA) is caused by mutations in the SMN (survival of motor neurons) gene and there is a correlation between disease severity and levels of functional SMN protein. Studies of structure-function relationships in SMN protein may lead to a better understanding of SMA pathogenesis. Self-association of the spinal muscular atrophy protein, SMN, is important for its function in RNA splicing. Biomolecular interaction analysis core analysis now shows that SMN self-association occurs via SMN regions encoded by exons 2b and 6, that exon 2b encodes a binding site for SMN-interacting protein-1 and that interaction occurs between exon 2- and 4-encoded regions within the SMN monomer. The presence of two separate self-association sites suggests a novel mechanism by which linear oligomers or closed rings might be formed from SMN monomers. 相似文献
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Parsons DW; McAndrew PE; Monani UR; Mendell JR; Burghes AH; Prior TW 《Human molecular genetics》1996,5(11):1727-1732
The gene for autosomal recessive spinal muscular atrophy (SMA) has been
mapped to 5q12 in a region that contains repeated markers and genes. Three
cDNAs that detect deletions in SMA patients have been reported. One of
these, the survival motor neuron (SMN) cDNA, is encoded by two genes (SMNT
and SMNC) which are distinguished by base changes in exons 7 and 8. Exon 7
of the SMNT gene is not detectable in approximately 95% of SMA cases, due
either to deletion or sequence conversion. There is limited information on
the mutations in SMA patients that have detectable SMNT, these are critical
for confirmation of SMNT as the SMA gene. Using SSCP analysis of the SMN
exons we screened our SMA patients that possess at least one intact SMNT
allele for mutations in SMNT. We identified one type I SMA patient with an
11 bp duplication in exon 6 which causes a frameshift and premature
termination of the deduced SMNT protein. Dosage and SSCP analysis of SMNT
in this family indicated that the father contributed a SMNT-deleted allele
to the affected child whereas the mother passed on the 11 bp exon 6
duplication SMNT allele. Analysis of RNA by RT-PCR conclusively
demonstrated that the 11 bp duplication is associated with the SMNT locus
and not SMNC. This mutation provides strong support for SMN as the
SMA-determining gene and indicates that disruption of SMNT on its own is
sufficient to produce a severe type I SMA phenotype.
相似文献
5.
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.
相似文献
6.
Spinal muscular atrophy (SMA) is a motor neuron disorder resulting from
anterior horn cell death. Survival motor neuron ( SMN ) is the SMA-
determining gene and is deleted or gene converted in >95% of SMA
patients. The SMN protein has a role in spliceosomal snRNP biogenesis and
has therefore been implicated indirectly in general cellular RNA processing
due to its unique sub-nuclear localization within structures termed 'gems',
which co-localize with spliceosomal factors within coiled bodies. In this
report, direct SMN RNA-binding activity, in addition to ssDNA and dsDNA
binding is demonstrated. The region of SMN encoded by exon 2 is necessary
and sufficient to mediate its nucleic acid-binding activities. This domain
is homologous to several nucleic acid-binding factors, including several
high mobility group (HMG) proteins. Additionally, previously reported SMN
missense mutations isolated from SMA patients demonstrated reduced
RNA-binding activity, suggesting that nucleic acid binding is functionally
significant.
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Bertrandy S Burlet P Clermont O Huber C Fondrat C Thierry-Mieg D Munnich A Lefebvre S 《Human molecular genetics》1999,8(5):775-782
Spinal muscular atrophy (SMA) is a common autosomal recessive disorder that results in the degeneration of spinal motor neurons. SMA is caused by alterations of the survival motor neuron ( SMN ) gene which encodes a novel protein of hitherto unclear function. The SMN protein associates with ribonucleoprotein particles involved in RNA processing and exhibits an RNA-binding capacity. We have isolated the zebrafish Danio rerio and nematode Caenorhabditis elegans orthologues and have found that the RNA-binding capacity is conserved across species. Purified recombinant SMN proteins from both species showed selectivity to poly(G) homopolymer RNA in vitro, similar to that of the human protein. Studying deletions of the zebrafish SMN protein, we defined an RNA-binding element in exon 2a, which is highly conserved across species, and revealed that its binding activity is modulated by protein domains encoded by exon 2b and exon 3. Finally, the deleted recombinant zebrafish protein mimicking an SMA frameshift mutation showed a dramatic change in vitro in the formation of the RNA-protein complexes. These observations indicate that the RNA-binding capacity of SMN is an evolutionarily conserved function and further support the view that defects in RNA metabolism most likely account for the pathogenesis of SMA. 相似文献
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Spinal muscular atrophy (SMA) is the leading genetic cause of infantile death and caused by the loss of functional Survival Motor Neuron 1 (SMN1). The remaining copy gene, SMN2, is unable to rescue from disease because the primary gene product lacks the final coding exon, exon 7, due to an alternative splicing event. While SMNΔ7 is a rapidly degraded protein, exon 7 is not specifically required in a sequence-specific manner to confer increased functionality to this truncated protein. Based upon this molecular observation, aminoglycosides have been examined to artificially elongate the C-terminus of SMNΔ7 by "read-through" of the stop codon. An SMNΔ7 read-through event benefits intermediate mouse models of SMA. Here we demonstrate that delivery of a read-through inducing compound directly to the CNS can partially lessen the severity of a severe model of SMA (Smn(-/-); SMN2(+/+)), albeit not to the extent seen in the less severe model. This further demonstrates the utility of read-through inducing compounds in SMA. 相似文献
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Preimplantation genetic diagnosis of spinal muscular atrophy 总被引:7,自引:3,他引:7
Dreesen JC; Bras M; de Die-Smulders C; Dumoulin JC; Cobben JM; Evers JL; Smeets HJ; Geraedts JP 《Molecular human reproduction》1998,4(9):881-885
After Duchenne muscular dystrophy, spinal muscular atrophy (SMA) is the
most common severe neuromuscular disease in childhood. Since 1995,
homozygous deletions in exon 7 of the survival motor neuron (SMN) gene have
been described in >90-95% of SMA patients. However, the presence of a
highly homologous SMN copy gene complicates the detection of exon 7
deletions. This paper describes the adjustment and evaluation of an
established SMN exon 7 polymerase chain reaction (PCR) protocol at the
single cell level, and the first preimplantation genetic diagnosis (PGD) of
SMA with this PCR protocol. To determine PCR efficiency and allelic loss,
200 leukocytes of normal individuals, SMA carriers and patients, and 25
blastomeres were tested. The PCR efficiency of the SMN exon 7 and the
adjacent copy gene sequence, tested in the leukocytes, were 90% and 91%
respectively. No allelic loss was detected. One out of 25 blastomeres
tested revealed a negative PCR signal for the SMN exon 7 sequence. All 25
showed the copy gene sequence. PGD of SMA was offered to a couple with an
affected child homozygous for the SMN exon 7 deletion. After
intracytoplasmic sperm injection, four and five embryos could be genotyped
for the SMN exon 7 in two cycles respectively. After embryo transfer in the
second PGD cycle an ongoing gemelli pregnancy was achieved. This study
demonstrates that PGD for SMA is feasible when a previous child is
homozygous for the SMN exon 7 deletion.
相似文献
15.
An approximately 140-kb deletion associated with feline spinal muscular atrophy implies an essential LIX1 function for motor neuron survival
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Fyfe JC Menotti-Raymond M David VA Brichta L Schäffer AA Agarwala R Murphy WJ Wedemeyer WJ Gregory BL Buzzell BG Drummond MC Wirth B O'Brien SJ 《Genome research》2006,16(9):1084-1090
The leading genetic cause of infant mortality is spinal muscular atrophy (SMA), a clinically and genetically heterogeneous group of disorders. Previously we described a domestic cat model of autosomal recessive, juvenile-onset SMA similar to human SMA type III. Here we report results of a whole-genome scan for linkage in the feline SMA pedigree using recently developed species-specific and comparative mapping resources. We identified a novel SMA gene candidate, LIX1, in an approximately140-kb deletion on feline chromosome A1q in a region of conserved synteny to human chromosome 5q15. Though LIX1 function is unknown, the predicted secondary structure is compatible with a role in RNA metabolism. LIX1 expression is largely restricted to the central nervous system, primarily in spinal motor neurons, thus offering explanation of the tissue restriction of pathology in feline SMA. An exon sequence screen of 25 human SMA cases, not otherwise explicable by mutations at the SMN1 locus, failed to identify comparable LIX1 mutations. Nonetheless, a LIX1-associated etiology in feline SMA implicates a previously undetected mechanism of motor neuron maintenance and mandates consideration of LIX1 as a candidate gene in human SMA when SMN1 mutations are not found. 相似文献
16.
The childhood autosomal recessive disorder spinal muscular atrophy (SMA) is caused by mutations in the survival motor neuron (SMN) gene. SMN localizes diffusely in the cytoplasm and in distinct nuclear structures called Cajal bodies. Cajal bodies are believed to be the storage and processing sites of several ribonucleoproteins. Here, using a novel panel of SMN exon deletion constructs, we report a systematic analysis of internal targeting domains in the SMN protein. We demonstrate that the peptides encoded by exons 2b, 3 and 6 perform an integral role in the cellular targeting of SMN. In addition, we identify a nine amino acid motif within the highly conserved sequences of the exon 2b encoded domain that mediates Cajal body targeting and self-association. Deletion of this domain dramatically affects SMN activity and results in a dominant-negative clone. These results identify critical domains within the SMN protein and have an impact on our understanding of the SMN protein with regards to SMA as well as cellular biology. 相似文献
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目的对云南地区3049名育龄人群进行脊髓性肌萎缩症(spinal muscular atrophy,SMA)的携带者筛查,探讨本地区人群运动神经元存活基因(survival motor neuron,SMN)的拷贝数情况及携带频率。方法应用多重连接探针扩增技术(multiplex ligation-dependent probe amplification,MLPA)对SMN1及SMN2基因第7外显子的拷贝数进行检测,筛查出SMN1基因第7外显子拷贝数为1的SMA携带者。对双方均为携带者的夫妇提供产前诊断。结果在3049名育龄人群中,共检测出SMA携带者62例,携带率为1/49(2.03%)。男性携带率为1.91%(40/2094),女性携带率为2.30%(22/955),二者的差异无统计学意义(P>0.05)。SMN1杂合缺失占1.30%(41/3049),由SMN1转换为SMN2者占0.69%(21/3049)。SMN1等位基因的平均拷贝数为1.99。检出双方均为SMA携带者的夫妇2对,通过产前诊断避免了1例患病胎儿的出生。结论云南地区SMA男女携带者的频率无显著差异,符合常染色体隐性遗传模式。阐明SMA携带者的频率和SMN基因的拷贝数情况,可为遗传咨询和产前预防提供依据。 相似文献
19.
An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA) 总被引:26,自引:0,他引:26
Wirth B 《Human mutation》2000,15(3):228-237
Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons in the spinal cord, causing progressive weakness of the limbs and trunk, followed by muscle atrophy. SMA is one of the most frequent autosomal recessive diseases, with a carrier frequency of 1 in 50 and the most common genetic cause of childhood mortality. The phenotype is extremely variable, and patients have been classified in type I-III SMA based on age at onset and clinical course. All three types of SMA are caused by mutations in the survival motor neuron gene (SMN1). There are two almost identical copies, SMN1 and SMN2, present on chromosome 5q13. Only homozygous absence of SMN1 is responsible for SMA, while homozygous absence of SMN2, found in about 5% of controls, has no clinical phenotype. Ninety-six percent of SMA patients display mutations in SMN1, while 4% are unlinked to 5q13. Of the 5q13-linked SMA patients, 96.4% show homozygous absence of SMN1 exons 7 and 8 or exon 7 only, whereas 3. 6% present a compound heterozygosity with a subtle mutation on one chromosome and a deletion/gene conversion on the other chromosome. Among the 23 different subtle mutations described so far, the Y272C missense mutation is the most frequent one, at 20%. Given this uniform mutation spectrum, direct molecular genetic testing is an easy and rapid analysis for most of the SMA patients. Direct testing of heterozygotes, while not trivial, is compromised by the presence of two SMN1 copies per chromosome in about 4% of individuals. The number of SMN2 copies modulates the SMA phenotype. Nevertheless, it should not be used for prediction of severity of the SMA. 相似文献
20.
Velasco E; Valero C; Valero A; Moreno F; Hernandez-Chico C 《Human molecular genetics》1996,5(2):257-263
Spinal muscular atrophy is an autosomal recessive disorder which affects
about 1 in 10,000 individuals. The three clinical forms of SMA were mapped
to the 5q13 region. Three candidate genes have been isolated and shown to
be deleted in SMA patients: the Survival Motor Neuron gene (SMN), the
Neuronal Apoptosis Inhibitory Protein gene (NAIP) and the XS2G3 cDNA. In
this report we present the molecular analysis of the SMN exons 7 and 8 and
NAIP exon 5 in 65 Spanish SMA families. NAIP was mostly deleted in type I
patients (67.9%) and SMN was deleted in 92.3% of patients with severe and
milder forms. Most patients who lacked the NAIP gene also lacked the SMN
gene, but we identified one type II patient deleted for NAIP exon 5 but not
for SMN exons 7 and 8. Two other patients carried deletions of NAIP exon 5
and SMN exon 7 but retained the SMN exon 8. Three polymorphic variants from
the SMN gene, showing changes on the sequence of the centromeric (cBCD541)
and telomeric copies of the SMN gene, were found. In addition, we show
several genetic rearrangements of the telomeric SMN gene, which include
duplication of this gene in one normal chromosome, and putative gene
conversion events in affected and normal chromosomes. Altogether these
results corroborate the high genetic variability of the SMA region.
Finally, we have determined the ratio between the number of centromeric and
telomeric copies of the SMN gene in parents of SMA patients, showing that
the majority of parents of types II and III patients carried three or more
copies of the cBCD541 gene; we suggest a relationship between the number of
copies of cBCD541 and the disease phenotype.
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