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Characterization of survival motor neuron (SMNT) gene deletions in asymptomatic carriers of spinal muscular atrophy 总被引:14,自引:1,他引:13
Wang CH; Xu J; Carter TA; Ross BM; Dominski MK; Bellcross CA; Penchaszadeh GK; Munsat TL; Gilliam TC 《Human molecular genetics》1996,5(3):359-365
Previous reports have established that the telomeric copy of the survival
motor neuron (SMNT) gene and the intact copy of the neuronal apoptosis
inhibitory protein (NAIP) gene are preferentially deleted in patients with
spinal muscular atrophy (SMA). Although deletions or mutations in the SMNT
gene are most highly correlated with SMA, it is not clear to what extent
NAIP or other genes influence the SMA phenotype, or whether a small
fraction of SMA patients actually have functional copies of both SMNT and
NAIP. To evaluate further the part of SMNT in the development of SMA, we
analyzed 280 asymptomatic SMA family members for the presence or absence of
SMNT exons 7 and 8. We report the following observations: (i) 4% of the
sample harbored a polymorphic variant of SMNT exon 7 that looks like a
homozygous deletion; (ii) approximately 1% of the parents are homozygously
deleted for both exons 7 and 8; (iii) one asymptomatic parent lacking both
copies of SMNT exons 7 and 8 displays a 'subclinical phenotype'
characterized by mild neurogenic pathology; (iv) another asymptomatic
parent lacking both SMNT exons showed no signs of motor neuron disorder by
clinical and neurodiagnostic analyses. The demonstration of polymorphic
variants of exon 7 that masquerade as homozygous nulls, and the
identification of SMA parents who harbor two disease alleles, serve as a
caution to those conducting prenatal tests with these markers.
相似文献
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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.
相似文献
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Hahnen Eric; Forkert Randolf; Marke Christine; Rudnik-Schoneborn Sabine; Schonling Jutta; Zerres Klaus; Creavin T.; Wirth Brunhilde 《Human molecular genetics》1995,4(10):1927-1933
Proximal spinal muscular atrophy (SMA) is a common autosomalrecessive neuromuscular disorder characterized by degenerationof anterior horn cells in the spinal cord leading to weaknessand wasting of voluntary muscles. Here we present the molecularanalysis of both SMA candidate genes, the survival motor neurongene (SMN; exons 7 and 8) and the neuronal apoptosis inhibitoryprotein gene (NAIP; exons 5, 6 and 13), in 195 patients and348 parents of SMA families mainly of German origin. The SMNgene is homozygously deleted for both exons 7 and 8 or exon7 only in 96% of type I SMA, 94% of type II SMA and 82% of typeIII SMA as well as in 0.3% of SMA parents. The NAIP gene ishomozygously deleted in 46% of type I SMA, 17% of type II SMA,7% of type III SMA and 2% of SMA parents. The frequencies ofdeletions in patients for both genes, SMN and NAIP, correspondto those for the NAIP gene only. SMA patients of this serieswho did not show deletions were clinically Indistinguishablefrom deleted patients. In addition to one unaffected motherof a type II SMA patient, we found homozygous deletions of theSMN gene exons 7 and 8 in six further unaffected individuais,all sibs of type II and III patients. These belonged to fourfamilies with affected and unaffected sibs who showed identicalhaplotypes for all SMA flanking markers; therefore, we had regardedthese families as chromosome 5 unlinked. All seven unaffectedindividuals in whom we detected SMA deletions do not show anysigns of muscle weakness and are physically inconspicuous. Thelargest divergence between age at onset of an affected subjectand the present age of unaffected deleted sibs is four decadesnow. The occurrence of SMN deletions in unaffected individualssuggests that other genes or mechanisms may be necessary toproduce the SMA phenotype. 相似文献
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Alternative splicing is an essential process that produces protein diversity in humans. It is also the cause of many complex diseases. Spinal muscular atrophy (SMA), the second most common autosomal recessive disorder, is caused by the absence of or mutations in the Survival Motor Neuron 1 (SMN1) gene, which encodes an essential protein. A nearly identical copy of the gene, SMN2, fails to compensate for the loss of SMN1 because exon 7 is alternatively spliced, producing a truncated protein, which is unstable. SMN1 and SMN2 differ by a critical C-to-T substitution at position 6 of exon 7 in SMN2 (C6U transition in mRNA). This substitution alone is enough to cause an exon 7 exclusion in SMN2. Various cis- and trans-acting factors have been shown to neutralize the inhibitory effects of C6U transition. Published reports propose models in which either abrogation of an enhancer element associated with SF2/ASF or gain of a silencer element associated with hnRNP A1 is the major cause of exon 7 exclusion in SMN2. Most recent model suggests the presence of an EXtended INhibitory ContexT (Exinct) that is formed as a consequence of C6U transition in exon 7 of SMN2. In Exinct model, several factors may affect exon 7 splicing through cooperative interactions. Such regulation may be common to many alternatively spliced exons in humans. Recent advances in our understanding of SMN gene splicing reveals multiple challenges that are specific to in vivo regulation, which we now know is intimately connected with other biological pathways. 相似文献
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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
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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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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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Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy (SMA) 总被引:11,自引:5,他引:6
Hahnen E; Schonling J; Rudnik-Schoneborn S; Raschke H; Zerres K; Wirth B 《Human molecular genetics》1997,6(5):821-825
Spinal muscular atrophy (SMA) is a frequent autosomal recessive
neurodegenerative disorder leading to weakness and atrophy of voluntary
muscles. The survival motor neuron gene (SMN) is a strong candidate for SMA
and present in two highly homologous copies (telSMN and cenSMN) within the
SMA region (5q11.2-q13.3). More than 90% of SMA patients show homozygous
deletions of at least exon 7 of telSMN, whereas absence of cenSMN seems to
have no clinical consequences. In 23 non-deleted SMA patients, we searched
for intragenic mutations of the SMN genes in exons 1-7 and the promotor
region by single strand conformation analysis. We identified two different
missense mutations, S2621 and T2741, in exon 6 of telSMN in three
independent SMA families, providing further evidence for the telSMN gene as
a SMA determining gene. Both mutations, as well as two previously described
mutations (Y272C and G279V) are located within a highly conserved interval
from codon 258 to codon 279 which seems to be an important functional
domain of the telSMN protein. Recently, this region has been shown to
contain a tyrosine/glycine-rich motif, which is also present in various RNA
binding proteins, suggesting a potential role of SMN in RNA metabolism.
Missense mutations might be useful for in vivo and transgenic experiments
and further investigations on understanding the function of the telSMN
protein.
相似文献
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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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Ogino S Gao S Leonard DG Paessler M Wilson RB 《European journal of human genetics : EJHG》2003,11(3):275-277
Most carriers of autosomal recessive spinal muscular atrophy (SMA) have only one copy of SMN1 because of SMN1 gene deletions or gene conversions from SMN1 to SMN2, which has only one base difference in coding sequence from SMN1. Using SMN gene dosage analysis, we determined the copy numbers of SMN1 and SMN2 in the general population as well as in SMA patients and carriers. Increased SMN1 copy number is associated with decreased SMN2 copy number in the general population; that is, SMN2 copy number was decreased to one or zero copies in 11 of 13 individuals with three or four copies of SMN1, whereas only 71 of 164 individuals with two copies of SMN1 had one or zero copies of SMN2 (P<0.01). SMN2 copy number was increased to three or four in a subset of SMN1 deletion/conversion carriers, and in most SMA patients with a milder phenotype. In conclusion, our data provide evidence that gene conversion from SMN2 to SMN1 occurs, and that SMN1 converted from SMN2 is present in the general population. 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.
相似文献
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Shin S Park SS Hwang YS Lee KW Chung SG Lee YJ Park MH 《Journal of Korean medical science》2000,15(1):93-98
Childhood-onset proximal spinal muscular atrophies (SMAs) are an autosomal recessive, clinically heterogeneous group of neuronopathies characterized by selective degeneration of anterior horn cells. The causative genes to be reported are survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes. The deletion of telomeric copy of SMN (SMN(T)) gene was observed in over 95% of SMAs. The deletion rate of NAIP gene is 20-50% according to disease severity. The objective of this article is to genetically characterize the childhood-onset spinal muscular atrophy in Koreans. Five Korean families (14 constituents containing 5 probands) with SMA were included in this study. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used for the deletion analysis of SMN(T). Multiplex PCR method was used for NAIP analysis. Four probands showed deletion of SMNT gene. Deletion of SMN(C) (centromeric SMN) gene was found in one proband who did not show the deletion of SMN(T) gene and in the father of one proband who showed the deletion of SMN(T) gene. The deletion of NAIP gene was not found among all the studied individuals. The extent of deletion in Koreans was smaller than that in other studied population. PCR-RFLP deletion analysis can be applied to diagnose SMA and make a prenatal diagnosis. 相似文献