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PubMed1998

Identification of a novel missense mutation of the SMN(T) gene in two siblings with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations in the telomeric copy of the survival motor neuron (SMN(T)) gene. Over 90% of SMA patients harbor a deletion of SMN(T), but relatively few base-pair mutations have been reported. We report here a novel G279C mutation with a G to T transversion on exon 7 (nucleotide position 868) of SMN(T). Another missense mutation has been reported recently on position 869. The fact that two mutations on the same codon both result in SMA suggest a functional significance of this amino acid within the SMN protein.

Amino Acid Substitution↗
PubMedDate not supplied

[Indirect molecular-genetic family study and prenatal diagnosis of infantile spinal muscular atrophy].

Spinal muscular atrophy is one of the most common severe inherited diseases in childhood and especially the acute form of type I (Werdnig-Hoffmann) results in early death. Recently, all three types of childhood-onset SMA have been mapped to chromosome 5. Since then heterozygote detection in siblings and prenatal diagnosis of SMA type I is possible by indirect genetic analysis. As the gene and the mutation responsible for the disease have not yet been cloned, DNA analysis results in a risk figure which depends on the informativity and recombination frequency of the flanking markers studied.

Chorionic Villi Sampling↗
PubMed1999

Progressive spinal muscular atrophies.

Spinal muscular atrophy is the most common autosomal-recessive genetic disorder lethal to infants. It was first described in the 1890s. Since then our understanding of the disorder has progressed significantly. Progression of the disease is due to loss of anterior horn cells, thought to be caused by apoptosis. Diagnosis is based on the course of the illness, as well as certain changes seen on nerve and muscle biopsy and electrodiagnostic studies. More recently, our understanding of the genetics of this disorder has provided a noninvasive approach to diagnosis. This method of testing has its downside, but the quest for a more sensitive analysis is still underway. Even though our knowledge of this disease has come a long way since its first recognition, the therapies available to these children are still only supportive. Again, researchers eagerly look for new therapeutic interventions to allow for improved quality of life and an extended life span.

Disease Progression↗
PubMed1994

[Physical study of big fragments and search strategy of genes. Application to locus of infant spinal muscular atrophies].

Spinal muscular atrophies (SMA) represent the second most common fatal autosomal recessive disorder after cystic fibrosis. Childhood SMAs are divided into severe (type I) and mild forms (types II and III). By a combination of genetic and physical mapping, a YAC contig of the 5q13 region spanning the disease locus was constructed that showed the presence of low copy-repeats in this region. Allele segregation was analyzed at the closest genetic loci detected by markers C212 and C272 in 201 SMA families. Inherited and de novo deletions were observed in 10 SMA patients. Moreover, deletions were strongly suggested in at least 18% of SMA type I patients by the observation of marked heterozygosity deficiency for the loci studied. These results indicate that deletion events are statistically associated with the severe form of SMA.

Chromosome Mapping↗
PubMed2002

Epidural anaesthesia in a child with possible spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a rare lower motor neurone disease in which anaesthetic management is often difficult as a result of muscle weakness and hypersensitivity to neuromuscular blocking agents. Neuraxial anaesthesia is controversial in these patients; however, some cases have been reported in which neuraxial anaesthesia has been used without neurological sequelae. We describe a 7-year-old patient with possible SMA scheduled for a Grice-arthrodesis. Because of previous prolonged postoperative drowsiness and poor oral intake, we decided to use an epidural technique with sevoflurane sedation and spontaneous ventilation to avoid the use of muscle relaxants and systemic opioids and consequently admission to the intensive care unit. After 3 days, the epidural analgesia was stopped and the patient regained her preoperative motor function within 5 h. Despite the controversy surrounding the use of neuraxial techniques in neuromuscular disease, we found no well-founded basis for this in patients with SMA in the literature.

Anesthesia, Epidural↗
PubMed1999

Spinal muscular atrophy.

Spinal muscular atrophy is a common cause of disability in childhood and is characterized by weakness and wasting of voluntary muscle. It is frequently fatal. The gene for this disorder has been identified as the SMN gene and is part of a highly complex duplicated region of chromosome 5 that is subject to a high rate of gene deletion and gene conversion. The severity of muscle weakness correlates with the amount of full-length SMN protein produced. Molecular genetic studies support a model in which patients are compound heterozygotes of deleted and converted alleles that predicts a progressively decreasing amount of protein product with severity of muscle weakness. The function of SMN is beginning to be understood and it appears to be involved in ribonucleoprotein biogenesis and thus indirectly in post-transcriptional processing of mRNA. There are theoretical grounds for motor neurons having a cell-specific vulnerability to disturbances of mRNA processing and transport and these are briefly reviewed.

Animals↗
PubMed2005

Challenges and opportunities in clinical trials for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the most common fatal neuromuscular disease of infancy. SMA type I is the most severe and mortality is usually due to respiratory failure. In type II the disability is of later onset and less severe, and prognosis has improved primarily due to supportive care. Type III is the mildest form with onset usually of weakness in adolescence or young adulthood. SMA is an autosomal recessive disorder with deletions or mutations of the gene at the 5 q11 locus. There is no specific prevention or treatment, but current progress toward potential therapies has been substantial and several candidates including histone deacetylase (HDAC) inhibitors are under consideration for further evaluation. The authors sought to address the challenges and opportunities for testing new therapies for SMA.

Child↗
PubMed1997

Correlation between severity and SMN protein level in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons of the spinal cord. Three different forms of childhood SMA have been recognized on the basis of age at onset and clinical course: Werdnig-Hoffmann disease (type-1), the intermediate form (type-II) and Kugelberg-Welander disease (type-III). A gene termed 'survival of motor neuron' (SMN) has been recognized as the disease-causing gene in SMA. SMN encodes a protein located within a novel nuclear structure and interacts with RNA-binding proteins. To elucidate the molecular mechanism underlying the pathogenesis of the disease, we examined the expression of the SMN gene in both controls and SMA patients by western blot and immunohistochemical analyses using antibodies raised against the SMN protein. The present study shows a marked deficiency of the SMN protein in SMA.

Blotting, Western↗
PubMed1999

Essential role for the tudor domain of SMN in spliceosomal U snRNP assembly: implications for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neurodegenerative disease of spinal motor neurons caused by reduced levels of functional survival of motor neurons (SMN) protein. SMN is part of a macromolecular complex that contains the SMN-interacting protein 1 (SIP1) and spliceosomal Sm proteins. Although it is clear that SIP1 as a component of this complex is essential for spliceosomal uridine-rich small ribonucleoprotein (U snRNP) assembly, the role of SMN and its functional interactions with SIP1 and Sm proteins are poorly understood. Here we show that the central region of SMN comprising a tudor domain facilitates direct binding to Sm proteins. Strikingly, the SMA-causing missense mutation E134K within the tudor domain severely reduced the ability of SMN to interact with Sm proteins. Moreover, antibodies directed against the tudor domain prevent Sm protein binding to SMN and abolish assembly of U snRNPs in vivo. Thus, our data show that SMN is an essential U snRNP assembly factor and establish a direct correlation between defects in the biogenesis of U snRNPs and SMA.

Animals↗
PubMed2001

Six unaffected livebirths following preimplantation diagnosis for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a severe neurodegenerative autosomal recessive disorder, second only in frequency to cystic fibrosis. In its most severe form, SMA type I (Werdnig-Hoffman), death invariably ensues before age 2 years from respiratory failure or infection. Around 98% of clinical cases of SMA are caused by the homozygous absence of a region of exons 7 and 8 of the telomeric copy of the SMN gene (SMN1) on chromosome 5. We have developed a novel means of preimplantation diagnosis of SMA using a nested polymerase chain reaction (PCR) amplification of exon 7 of SMN, followed by a HinfI restriction digest of the PCR product enabling the important SMN1 gene to be distinguished from the centromeric SMN2 gene which has no clinical phenotype. This method was designed to reduce the likelihood of misdiagnosis. Five couples were treated using this method. Four proceeded to embryo transfer which resulted in six liveborns (one singleton, one twin and one triplet), all free of SMA. Embryo transfer was not performed in one cycle because of PCR contamination.

Adult↗
PubMed1996

[The contribution of molecular genetics to the study of spinal muscular atrophy].

Spinal muscular atrophies constitute a group of hereditary diseases characterized by degeneration of the anterior horn of the spinal cord. Molecular studies began in 1990 with the location of the genome region responsible for the disease in chromosome 5q13. New directions for research were opened in 1995 with the identification of the affected region in the survival motor neuron (SMN) genes and the neuronal apoptosis inhibitory protein genes. A main feature of these genes is that they are duplicate, forming part of two elements (centromeric and telomeric) that include mini-satellites that are also repeated, making this zone particularly unstable. The molecular abnormalities found in patients are a consequence of that instability: gene deletions and conversions in the SMN gene have been described independently of whether symptoms were severe or not. Molecular data make it possible to confirm the clinical diagnosis of most patients and to provide certain prenatal diagnosis for couples that are at high risk of passing on the disorder. Determining both the function of these genes and their pathogenesic role will help to ground new therapeutic strategies that will prevent or detain motor neuron degeneration.

Apoptosis↗
PubMed2005

Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a motoneuron disease caused by reduced levels of survival motoneuron (SMN) protein. Previous studies have assigned SMN to uridine-rich small nuclear ribonucleoprotein particle (U snRNP) assembly, splicing, transcription, and RNA localization. Here, we have used gene silencing to assess the effect of SMN protein deficiency on U snRNP metabolism in living cells and organisms. In HeLa cells, we show that reduction of SMN to levels found in SMA patients impairs U snRNP assembly. In line with this, induced silencing of SMN expression in Xenopus laevis or zebrafish arrested embryonic development. Under less severe knock-down conditions, zebrafish embryos proceeded through development yet exhibited dramatic SMA-like motor axon degeneration. The same was observed after silencing two other essential factors in the U snRNP assembly pathway, Gemin2 and pICln. Importantly, the injection of purified U snRNPs into either SMN- or Gemin2-deficient embryos of Xenopus and zebrafish prevented developmental arrest and motoneuron degeneration, respectively. These findings suggest that motoneuron degeneration in SMA patients is a direct consequence of impaired production of U snRNPs.

Animals↗
PubMed2006

Multiplex ligation-dependent probe amplification improves diagnostics in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by decreased levels of survival motor neuron protein (SMN). In the majority of cases, this decrease is due to absence of the SMN1 gene. Multiplex ligation-dependent probe amplification (MLPA) is a modern quantitative molecular method. Applied in SMA cases, it improves diagnostics by simultaneously identifying the number of copies of several target sequences in the SMN1 gene and in nearby genes. Using MLPA in clinical diagnostics, we have identified a previously unreported, partial deletion of SMN1 (exons 1-6) in two apparently unrelated Swedish families. This mutation would not have been detected by conventional diagnostic methods. This paper illustrates the broad clinical and genetic spectrum of SMA and includes reports of MLPA results and clinical descriptions of a patient with homozygous absence of SMN1 and only one SMN2 (prenatal onset SMA type 1), an asymptomatic woman with five SMN2 (lacking SMN1) and representative patients with SMA types 1, 2 and 3.

Adolescent↗
PubMed2003

A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a relatively common neurodegenerative disease caused by homozygous loss of the survival motor neuron 1 (SMN1) gene. Humans possess a linked, nearly identical gene, SMN2, which produces a functional SMN protein but at levels insufficient to compensate for loss of SMN1 (refs. 1,2). A C/T transition at position +6 in exon 7 is all that differentiates the two genes, but this is sufficient to prevent efficient exon 7 splicing in SMN2 (refs. 2,3). Here we show that the C/T transition functions not to disrupt an exonic splicing enhancer (ESE) in SMN1 (ref. 4), as previously suggested, but rather to create an exonic splicing silencer (ESS) in SMN2. We show that this ESS functions as a binding site for a known repressor protein, hnRNP A1, which binds to SMN2 but not SMN1 exon 7 RNA. We establish the physiological importance of these results by using small interfering RNAs to reduce hnRNP A protein levels in living cells and show that this results in efficient SMN2 exon 7 splicing. Our findings not only define a new mechanism underlying the inefficient splicing of SMN2 exon 7 but also illustrate more generally the remarkable sensitivity and precision that characterizes control of mRNA splicing.

Base Sequence↗
PubMed2001

A single strand conformation polymorphism-based carrier test for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder with a newborn prevalence of 1 in 10,000, and a carrier frequency of 1 in 40-60 individuals. The SMA locus has been mapped to chromosome 5q11.2-13. The disease is caused by a deletion of the SMN gene, often encompassing other genes and microsatellite markers. The SMN gene is present in two highly homologous copies, SMN1 and SMN2, differing at five nucleotide positions. Only homozygous SMN1 mutations cause the disease. The sequence similarity between the SMN1 and SMN2 genes can make molecular diagnosis and carrier identification difficult. We developed a sensitive and reliable molecular test for SMN1 carrier identification, by setting up a nonradioactive single strand conformation polymorphism (SSCP)-based method, which allows for the quantification of the amount of the SMN1 gene product with respect to a control gene. The assay was validated in 56 obligate (ascertained) carriers and 20 (ascertained) noncarriers. The sensitivity of the test is 96.4%, and its specificity, 98%. In addition, 6 of 7 SMA patients without homozygous deletions presented with a heterozygous deletion, suggesting a concomitant undetected point mutation on the nondeleted SMN1 allele. Therefore, the present test is effective for detecting compound hemizygote patients, for testing carriers in SMA families, and for screening for SMA heterozygotes in the general population.

Alleles↗
PubMed2006

A novel method for oral delivery of drug compounds to the neonatal SMNDelta7 mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a devastating motor neuron disease that is one of the leading genetic causes of infant mortality. Currently, there is no cure for SMA. Mouse models that genetically and phenotypically resemble SMA have been generated and have the potential to be used for the discovery of novel therapeutics. Oral administration is a commonly used mode of drug delivery in humans as well as in rodents. Unfortunately, there is no method of drug delivery that can accurately and reliably deliver drug compounds orally to neonatal mice. In this report, we describe a novel method to orally administer compounds to neonatal SMA mice. Oral delivery to neonatal mice, usually starting at postnatal day 4 (PND04), is both rapid and safe to the pup. Oral delivery of two different commonly used vehicle formulations, distilled water and 2-hydroxypropyl-beta-cyclodextrin, does not affect the survival of SMA mice. After oral delivery for 3 days, 5-bromo-2'-deoxyuridine could be detected in the kidneys, brains and spinal cords of treated non-SMA as well as SMA neonatal pups. In conclusion, we have developed a method by which drugs can be safely and reliably administered orally to neural targets of neonatal mice. This approach offers a simple and rapid means by which potential therapeutics for SMA can be identified.

Administration, Oral↗
PubMedDate not supplied

Polyglutamine tract expansion of the androgen receptor in a motoneuronal model of spinal and bulbar muscular atrophy.

Spinobulbar muscular atrophy (SBMA) is a late-onset disorder characterized by progressive muscle loss, degeneration of motoneurons in the spinal cord and brainstem, and partial androgen insensitivity. SBMA is directly correlated with the expansion of CAG repeats encoding a polyglutamine tract (polyQ) of extended length. The identification of polyQ expansion in SBMA led to the discovery of an entire class of neurodegenerative disorders. In fact, at least eight different diseases, including Huntington's disease, share a common molecular mechanism involving an expansion of a polyQ tract within different proteins. The elongated polyQ tract causes a toxic gain of function in the mutant protein and is associated with the formation of intracellular aggregates, whose pathogenetic role has not been fully established yet. Our observations in a motoneuron cell line (NSC34), indicate that the expression of the androgen receptor (AR) carrying the elongated polyQ tract (AR-Q48) has a toxic effect in aggregate-independent manner. In fact, in basal condition, AR-Q48 shows a cytoplasmic diffuse distribution, yet it reduces the viability of transfected NSC34. In contrast, testosterone treatment, while inducing aggregation of the mutant AR, also increases cell viability. Aggregates in NSC34 are localized mainly in the perinuclear region and occasionally in the neuropil, whereas no nuclear aggregate has ever been found. Further observations of the minor subset of cells showing neuropil aggregates, reveal an alteration of the neurite morphology, suggesting a different role of the two types of cytoplasmic aggregates.

Humans↗
PubMed1997

Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a motor neuron disease characterized by degeneration of the anterior horn cells of the spinal cord. It is a common fatal autosomal recessive disorder and linkage studies have identified two candidate genes, SMN and NAIP, both on chromosome 5q13. Although NAIP protein is known to have an anti-apoptotic function, the function of SMN has been unclear and it shows no significant sequence similarity to any other protein. The SMN gene is deleted or interrupted on both chromosomes in nearly all SMA patients. Here we show that SMN interacts with Bcl-2, another anti-apoptotic protein, and that co-expression of SMN with Bcl-2 confers a synergistic preventive effect against Bax-induced or Fas-mediated apoptosis, although SMN itself has only a weak anti-apoptotic activity. SMN(Y272C), which carries a missense mutation and was found in an SMA patient who exceptionally retained SMN on one allele, exerts no synergism with Bcl-2. Furthermore, the product of a truncated transcript lacking exon 7, which was derived from an SMN gene carrying an intragenic mutation or from the SMN copy gene cBCD541 retained in all SMA patients, had no synergistic activity but instead had a dominant-negative effect on full-length SMN. Our results indicate that an absent or decreased anti-apoptotic activity of SMN in concert with Bcl-2 underlies the pathogenesis of SMA.

Animals↗