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PubMed1997

Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy (SMA).

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.

Adolescent↗

PubMed2000

Animal models of spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA) is the second most common autosomal recessive inherited disorder in humans. It is the most common genetic cause of infant mortality. As yet, there is no cure for this neuromuscular disorder which affects the lower motor neurons and proximal muscles of the limbs and trunk. In the last decade, significant advances have been made in understanding this disease, from linkage analysis to isolating the defective gene and identifying its protein product. This review summarizes the most recent advance in SMA research: the development of animal models of the disease, in particular mouse models of SMA. The SMA mice that we describe here present with symptoms similar to those seen in SMA patients. They promise to further the understanding of the molecular basis of this disease and demonstrate the feasibility of using the intact SMN2 gene, found in all SMA patients, as a means of treating this disorder.

Animals↗

PubMed2000

The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA) is a common motor neuron disease in humans and in its most severe form causes death by the age of 2 years. It is caused by defects in the telomeric survival motor neuron gene ( SMN1 ), but patients retain at least one copy of a highly homologous gene, centromeric SMN ( SMN2 ). Mice possess only one survival motor neuron gene ( Smn ) whose loss is embryonic lethal. Therefore, to obtain a mouse model of SMA we created transgenic mice that express human SMN2 and mated these onto the null Smn (-/-)background. We show that Smn (-/-); SMN2 mice carrying one or two copies of the transgene have normal numbers of motor neurons at birth, but vastly reduced numbers by postnatal day 5, and subsequently die. This closely resembles a severe type I SMA phenotype in humans and is the first report of an animal model of the disease. Eight copies of the transgene rescues this phenotype in the mice indicating that phenotypic severity can be modulated by SMN2 copy number. These results show that SMA is caused by insufficient SMN production by the SMN2 gene and that increased expression of the SMN2 gene may provide a strategy for treating SMA patients.

Animals↗

PubMed2003

Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA) is a common neuromuscular disorder causing infant death in half of all patients. Homozygous absence of the survival motor neuron gene (SMN1) is the primary cause of SMA, while SMA severity is mainly determined by the number of SMN2 copies. One SMN2 copy produces only about 10% of full-length protein identical to SMN1, whereas the majority of SMN2 transcripts is aberrantly spliced due to a silent mutation within an exonic splicing enhancer in exon 7. However, correct splicing can be restored by over-expression of the SR-like splicing factor Htra2-beta 1. We show that in fibroblast cultures derived from SMA patients treated with therapeutic doses (0.5-500 microM) of valproic acid (VPA), the level of full-length SMN2 mRNA/protein increased 2- to 4-fold. Importantly, this up-regulation of SMN could be most likely attributed to increased levels of Htra2-beta 1 which facilitates the correct splicing of SMN2 RNA as well as to an SMN gene transcription activation. Especially at low VPA concentrations, the restored SMN level depended on the number of SMN2 copies. Moreover, VPA was able to increase SMN protein levels through transcription activation in organotypic hippocampal brain slices from rats. Finally, VPA also increased the expression of further SR proteins, which may have important implications for other disorders affected by alternative splicing. Since VPA is a drug highly successfully used in long-term epilepsy therapy, our findings open the exciting perspective for a first causal therapy of an inherited disease by elevating the SMN2 transcription level and restoring its correct splicing.

Animals↗

PubMed2007

Stat5 constitutive activation rescues defects in spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA) is a motor neuron degeneration disorder for which there is currently no effective treatment. Here, we report three compounds (sodium vanadate, trichostatin A and aclarubicin) that effectively enhance SMN2 expression by inducing Stat5 activation in SMA-like mouse embryonic fibroblasts and human SMN2-transfected NSC34 cells. We found that Stat5 activation enhanced SMN2 promoter activity with increase in both full-length and deletion exon 7 SMN transcripts in SMN2-NSC34 cells. Knockdown of Stat5 expression disrupted the effects of sodium vanadate on SMN2 activation but did not influence SMN2 splicing, suggesting that Stat5 signaling is involved in SMN2 transcriptional regulation. In addition, constitutive activation of Stat5 mutant (Stat5A1*6) profoundly increased the number of nuclear gems in SMA-patient lymphocytes and reduced SMA-like motor neuron axon outgrowth defects. These results demonstrate that Stat5 signaling could be a possible pharmacological target for treating SMA.

Aclarubicin↗

PubMed2001

Coilin forms the bridge between Cajal bodies and SMN, the spinal muscular atrophy protein.

Spinal muscular atrophy (SMA) is a genetic disorder caused by mutations in the human survival of motor neuron 1 gene, SMN1. SMN protein is part of a large complex that is required for biogenesis of various small nuclear ribonucleoproteins (snRNPs). Here, we report that SMN interacts directly with the Cajal body signature protein, coilin, and that this interaction mediates recruitment of the SMN complex to Cajal bodies. Mutation or deletion of specific RG dipeptide residues within coilin inhibits the interaction both in vivo and in vitro. Interestingly, GST-pulldown experiments show that coilin also binds directly to SmB'. Competition studies show that coilin competes with SmB' for binding sites on SMN. Ectopic expression of SMN and coilin constructs in mouse embryonic fibroblasts lacking endogenous coilin confirms that recruitment of SMN and splicing snRNPs to Cajal bodies depends on the coilin C-terminal RG motif. A cardinal feature of SMA patient cells is a defect in the targeting of SMN to nuclear foci; our results uncover a role for coilin in this process.

Amino Acid Sequence↗

PubMedDate not supplied

Multiplex nested PCR for preimplantation genetic diagnosis of spinal muscular atrophy.

OBJECTIVE: Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder caused in most patients by homozygous deletion of the SMN1 gene. For a carrier couple at a 25% risk of affected offspring, preimplantation genetic diagnosis (PGD) offers an alternative to prenatal diagnosis and termination of affected pregnancies. Our objective was to develop an accurate and reliable single-cell multiplex nested PCR analysis for PGD of SMA. METHODS: The method was developed on single blood leukocytes, obtained from healthy controls and an adult SMA type III patient with a known homozygous deletion of SMN1 exon 7 and 8. Multiplex nested PCR on single cells was used to co-amplify exons 7 and 8 of SMN. Additional multiplexing was performed with the ZFX/ZFY gene for sexing. Following successful establishment of the multiplex nested PCR protocol in single leukocytes, the technique was employed for PGD in 4 patients for a total of 7 cycles. In 2 patients, sexing was simultaneously performed using ZFX/ZFY. RESULTS: 220 single leukocytes from a normal individual and 220 from an SMA patient were analyzed. Exon 7 of SMN1 was amplified in 99% of normal single leukocytes and in none of the SMA-affected leukocytes. Exon 7 of SMN2 was amplified in 100% of both normal and SMA-affected leukocytes. Exon 8 of SMN1 was amplified in 98% of normal cells and in none of the SMA-affected leukocytes. Exon 8 of SMN2 was amplified in 96% of both normal and SMA-affected leukocytes. Amplification efficiency was 99% for ZFX/ZFY. There were no false-negative results and no contamination was detected in all wash-drop blanks tested. Seven PGD cycles were performed in 4 SMA-carrier couples with successful molecular analysis of 34 embryos and a total of 15 normal embryos transferred in 7 cycles. One clinical pregnancy has resulted in the delivery of a healthy male. Amniocentesis performed at 17 weeks confirmed the correct diagnosis for both SMA and sexing. CONCLUSIONS: These results suggest that our multiplex nested PCR protocol offers an efficient and accurate method for PGD of SMA while enabling the simultaneous analysis of an additional loci.

Adult↗

PubMed2006

[Eosinophil-derived neurotoxin as a new additional clinical marker in spinal muscular atrophies].

INTRODUCTION: Spinal muscular atrophies (SMA) are group of neuromuscular disorders characterized by degeneration of motorneurons in anterior column of medulla spinalis, and sometimes in motoneurons of cranial nerves and the brain. Causes of SMAs are mutations in genes encoding for SMN, SIP and NAIP that are very low in motorneurons of these patients. Ribonucleases (RNases) are enzymes that depolimerize RNA and may destabilize DNA. AIM: The objective of this study was to determine ribonuclease activity in serum and urine of SMA patients. METHODS: RNases were purified by anion-kation-exchange chromatographies, and HPLC, and their activity was measured by immunodetection using specific antibodies against rinonucleases in presence of RNA as a substrate. RESULTS: Eosinophil-derived neurotoxin (EDN) activity iin serum of SMA patients was 5.6, 3.8 and 2.6 higher in type I, II and III comparing with control group. RNase inhibitor activity in serum of the same patients was 3.0 and 2.4 lower in type I and II vs. Control group, but in type III was unchanged. Similar results are found in urine of the same patients. CONCLUSION: Increased serum and urin EDN activities in SMA patients could be used as a new additional clinical marker in their diagnosis.

Biomarkers↗

PubMedDate not supplied

Allele distribution of D5S125, MAP1B5' and D5S679 microsatellite markers in Turkish spinal muscular atrophy families.

Spinal muscular atrophy (SMA) is an autosomal recessive disease and one of the most common genetic causes of death in childhood. The gene for SMA has been mapped to chromosome 5q11.2-13.3. Chromosomal distribution of the alleles of D5S125, MAP1B5' and D5S679 polymorphic microsatellite markers in 14 unrelated Turkish SMA families have been determined. It is observed that the A9 allele of D5S679 has a significant (chi 2: 3.41 p: 0.065) non-random association with mutant chromosomes.

Alleles↗

PubMed1995

The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy.

The spinal muscular atrophies (SMAs), characterized by spinal cord motor neuron depletion, are among the most common autosomal recessive disorders. One model of SMA pathogenesis invokes an inappropriate persistence of normally occurring motor neuron apoptosis. Consistent with this hypothesis, the novel gene for neuronal apoptosis inhibitory protein (NAIP) has been mapped to the SMA region of chromosome 5q13.1 and is homologous with baculoviral apoptosis inhibitor proteins. The two first coding exons of this gene are deleted in approximately 67% of type I SMA chromosomes compared with 2% of non-SMA chromosomes. Furthermore, RT-PCR analysis reveals internally deleted and mutated forms of the NAIP transcript in type I SMA individuals and not in unaffected individuals. These findings suggest that mutations in the NAIP locus may lead to a failure of a normally occurring inhibition of motor neuron apoptosis resulting in or contributing to the SMA phenotype.

Amino Acid Sequence↗

PubMed1999

High incidence of a survival motor neuron gene/cBCD541 gene ratio of 2 in Japanese parents of spinal muscular atrophy patients: a characteristic background of spinal muscular atrophy in Japan?

Most spinal muscular atrophy (SMA) patients lack the survival motor neuron gene (SMN). However, the patients retain at least one copy of the cBCD541 gene (BCD), which is highly homologous with SMN. Here, we determined the SMN/BCD copy number ratios (the S/B ratios) of 12 parents of Japanese SMA patients with a homozygous SMN deletion, using competitive oligonucleotide priming polymerase chain reaction. We identified an S/B ratio of 2 in 25% of the parents examined, whereas less than 2% of parents of SMA patients in Western populations have an S/B ratio of 2. The high incidence of an S/B ratio of 2 in Japanese parents of SMA patients may reflect the characteristic genetic background of SMA in Japan.

Female↗

PubMed2005

SMN1 deletions among singaporean patients with spinal muscular atrophy.

INTRODUCTION: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterised by degeneration of spinal cord anterior horn cells, leading to muscular atrophy. It is the second most frequent autosomal recessive disease among Caucasian populations with a prevalence of between 1 in 6000 and 1 in 10,000 live births, and a carrier frequency of about 1 in 50. The International SMA Consortium classification defines several types of SMA depending on the age of onset and clinical severity. In the past, the diagnosis of SMA was confirmed by muscle biopsy and, sometimes, electromyography. In 1990, SMA was linked to the 5q13 region of chromosome 5. In 1995, it was found that >95% of patients with SMA have homozygous deletions of exons 7 and 8 of the survival motor neurone 1 (SMN1) gene, one of the candidate genes identified within 5q13. The purpose of our study was to determine the frequency of SMN1 deletions in patients with known SMA and the impact of this on the diagnosis of SMA. MATERIALS AND METHODS: Molecular analysis was performed on stored DNA and case notes were reviewed retrospectively. RESULTS: Twenty-two (91.7%) out of 24 patients with all types of SMA were homozygously deleted for exons 7 and/or 8 of SMN1. We also report our experience with prenatal diagnosis of SMA. CONCLUSIONS: Molecular studies can replace conventional investigations for SMA and have made the option of prenatal diagnosis possible for couples at risk.

Adult↗

PubMed2000

An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA).

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.

Amino Acid Sequence↗

PubMedDate not supplied

[Identification of T274I mutation in the SMN1 gene in a patient with spinal muscular atrophy].

Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterised by degeneration of motor neurones in the spinal cord. The symptoms of the disease are determinated by mutations of SMN1 gene. About 98% of SMA patients show homozygous absence of exon 7 SMN1 gene, the rest carry small intragenic mutations. Molecular analysis of the presence of exon 7 SMN1 gene deletion is considered as the screening test for SMA. We present a case report of a 9 years old girl with progressive muscular weakness of limbs and trunk. Clinical examination followed by electromyography and muscle biopsy was interpreted as a diagnostic of SMA 3. Molecular analysis did not reveal deletion of exon 7 SMN1 gene. Extended molecular diagnostics using direct sequencing showed missence mutation T2741. Thus, the absence of homozygous deletion of exon 7 SMN1 gene does not exclude SMA diagnosis. All patients fulfilling the diagnostic criteria for SMA, as defined by the International SMA Consortium, without deletion of exon SMN1 gene, should be analysed using direct sequencing.

Biopsy↗

PubMed1995

A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients.

Spinal muscular atrophy (SMA) is a frequent autosomal recessive disease characterized by degeneration of the motor neurons of the spinal cord causing proximal paralysis with muscle atrophy. The region on chromosome 5q13 encompassing the disease gene is particularly unstable and prone to large-scale deletions whose characterization recently led to the identification of the survival motor neuron (SMN) gene. We now present a genetic analysis of 54 unrelated Spanish SMA families that has revealed a 4-basepair (bp) deletion (AGAG) in exon 3 of SMN in four unrelated patients. This deletion, which results in a frameshift and a premature stop codon, occurs on the same haplotype background, suggesting that a single mutational event is involved in the four families. The other patients showed either deletions of the SMN gene (49/54) or a gene conversion event changing SMN exon 7 into its highly homologous copy (cBCD541, 1/54). This observation gives strong support to the view that mutations of the SMN gene are responsible for the SMA phenotype as it is the first frameshift mutation reported in SMA.

Base Sequence↗

PubMed2003

High incidence of SMN1 gene deletion in Moroccan adult-onset spinal muscular atrophy patients.

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuropathy characterized by selective degeneration of anterior horn cells of the spinal cord. Childhood SMA is divided into three types (I-III) on the basis of age of onset and severity. These disorders have been linked to the 5q13 region, where mutations in the Survival Motor Neuron 1 (SMN1) gene have been found in affected individuals. In the case of adult-onset SMA (type IV), on the other hand, reports of homozygous absence of SMN1 gene have been rare. We conducted deletion analysis of SMN and a neighboring gene, NAIP (neuronal apoptosis inhibiting protein). Among 54SMA patients (types I-IV), all of Moroccan origin, Exon 7 of the SMN1 gene was homozygously absent in 100% of type I, 90% of type II, 74% of type III and 80% of type IV SMA patients. Deletion of SMN1 exon 8 was detected in 100% of type I, 53% of type II, 53% of type III and 80% of type IV patients. NAIP exon 5 was homozygously deleted in 67% of type I, 32% of type II, 5% of type III and 20% of type IV SMA patients. Thirty control individuals who were studied had normal SMN1 and NAIP genes. Our results show a high incidence of SMN1 gene deletion in adult-onset SMA patients indicating that SMN1 is the autosomal recessive adult SMA-causing gene. While NAIP is commonly deleted in SMA, this is unlikely to affect disease severity; it was deleted in two adult SMA patients with mild phenotypes.

Adult↗

PubMed1998

Maternal mosaicism for a second mutational event in a type I spinal muscular atrophy family.

Spinal muscular atrophy (SMA) is a common fatal motor-neuron disorder characterized by degeneration of the anterior horn cells of the spinal cord, which results in proximal muscle weakness. Three forms of the disease, exhibiting differing phenotypic severity, map to chromosome 5q13 in a region of unusually high genomic variability. The SMA-determining gene (SMN) is deleted or rearranged in patients with SMA of all levels of severity. A high de novo mutation rate has been estimated for SMA, based on the deletion of multicopy microsatellite markers. We present a type I SMA family in which a mutant SMA chromosome has undergone a second mutation event. Both the occurrence of three affected siblings harboring this same mutation in one generation of this family and the obligate-carrier status of their mother indicate the existence of maternal germ-line mosaicism for cells carrying the second mutation. The existence of secondary mutational events and of germ-line mosaicism has implications for the counseling of SMA families undergoing prenatal genetic analysis.

Alleles↗

PubMed2002

Clinical and molecular diagnosis of spinal muscular atrophy.

The spinal muscular atrophies are a group of disorders characterized by flaccid limb weakness. It is necessary to differentiate these from other causes and identify the SMA variants. In classical SMA, majority of the patients shows homozygous deletion of the telomeric SMN gene (SMN1) on chromosome 5q. The availability of DNA analysis has allowed proper genetic counseling and prenatal diagnosis in the affected families. Application of newer techniques has enabled more accurate carrier detection. Our objective is to stress the variability in the clinical features and recent advances in the molecular diagnosis for SMA.

Genetic Carrier Screening↗