Prenatal Prediction of Spinal
Muscular Atrophy

Cobben, Jan-Hein; Scheffer, Hans; Visser, Marjolein; Steege, Gerrit van der; Verhey, J. B. B. M.; Osinga, Jan; Burton, M.; Mensink, Rgj; Grootscholten, P. M.; Kate, Leo P. ten; Buys, Chcm

doi:10.1159/000472204

Cited by 17 publications

(8 citation statements)

References 31 publications

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“…Given the fact that rare cases of SMA, particularly in females, show homozygous loss of SMN1, but no SMA phenotype (47,48), one could speculate that a sex-specific factor might differentially regulate Htra2-␤1 in these females and prevents them from getting SMA. Taken together, our results open the exciting possibility that SMA may be treated by agents that promote high levels of FL expression from SMN2.…”

Section: Discussionmentioning

confidence: 99%

Htra2-β 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 ( SMN2 )

Hofmann

Lorson

Stamm

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

292

253

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Spinal muscular atrophy (SMA), a common motor neuron disease in humans, results from loss of functional survival motor neuron (SMN1) alleles. A nearly identical copy of the gene, SMN2, fails to provide protection from SMA because of a single translationally silent nucleotide difference in exon 7. This likely disrupts an exonic splicing enhancer and causes exon 7 skipping, leading to abundant production of a shorter isoform, SMN2⌬7. The truncated transcript encodes a less stable protein with reduced self-oligomerization activity that fails to compensate for the loss of SMN1. This report describes the identification of an in vivo regulator of SMN mRNA processing. Htra2-␤1, an SR-like splicing factor and ortholog of Drosophila melanogaster transformer-2, promoted the inclusion of SMN exon 7, which would stimulate full-length SMN2 expression. Htra2-␤1 specifically functioned through and bound an AG-rich exonic splicing enhancer in SMN exon 7. This effect is not speciesspecific as expression of Htra2-␤1 in human or mouse cells carrying an SMN2 minigene dramatically increased production of full-length SMN2. This demonstrates that SMN2 mRNA processing can be modulated in vivo. Because all SMA patients retain at least one SMN2 copy, these results show that an in vivo modulation of SMN RNA processing could serve as a therapeutic strategy to prevent SMA. P roximal spinal muscular atrophy (SMA) is a neurodegenerative disorder with progressive paralysis caused by the loss of ␣-motor neurons in the spinal cord. With an incidence of 1 in 10,000 live births and a carrier frequency of 1 in 50, SMA is the second most common autosomal recessive disorder and the most frequent genetic cause of infantile death (1). SMA patients are subdivided into types I-III according to age of onset and achieved motor abilities (2). All three forms of proximal SMA are caused by mutations within the telomeric copy of the survival motor neuron gene, SMN1 (3). Some 96.4% of 5q-linked SMA patients show homozygous absence of SMN1 caused by deletions or gene conversions, whereas 3.6% display rare subtle mutations (3, 4). Homozygous absence of SMN2 is found in 5% of control individuals; however, loss of SMN2 has no phenotypic effect (3). SMN1 produces exclusively full-length (FL) SMN mRNA. In contrast, SMN2 expresses dramatically reduced FL and abundant levels of transcript lacking exon 7, SMN2⌬7. SMN2 is retained by all patients and a correlation between the SMN2 protein level and the disease state is established (5, 6). This spliced isoform encodes a truncated, less stable protein with reduced self-oligomerization activity (3,7,8). We have shown that inclusion of exon 7 in SMN1-derived transcripts and exclusion of this exon in SMN2-derived transcripts is determined by a single nucleotide difference at position ϩ6 in SMN exon 7 (C in SMN1; T in SMN2). This nucleotide difference is nonpolymorphic in the SMN2 gene and likely disrupts an exonic splicing enhancer (ESE) (9, 10).The removal of introns and joining of exons is performed by the spliceosome, a ma...

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Section: Discussionmentioning

confidence: 99%

Htra2-β 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 ( SMN2 )

Hofmann

Lorson

Stamm

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

292

253

View full text Add to dashboard Cite

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“…SMA has been linked to deletions or mutations of the survival of motor neuron (SMN) gene, which has been mapped as an inverted repeat to chromosome 5 at 5q13 (4). Homozygous absence of the telomeric copy (SMN1) correlates with development of SMA (5,6). By contrast, alterations within the centromeric SMN gene (SMN2) do not produce any known phenotype (4).…”

Section: Proximal Spinal Muscular Atrophy (Sma)mentioning

confidence: 99%

Modulation of Survival Motor Neuron Pre-mRNA Splicing by Inhibition of Alternative 3′ Splice Site Pairing

Lim

Hertel

2001

Journal of Biological Chemistry

148

114

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Spinal muscular atrophy is caused by the loss of functional survival motor neuron (SMN1) alleles. A translationally silent nucleotide transition in the duplicated copy of the gene (SMN2) leads to exon 7 skipping and expression of a nonfunctional gene product. It has been suggested that differential SMN2 splicing is caused by the disruption of an exonic splicing enhancer. Here we show that the single nucleotide difference reduces the intrinsic strength of the 3 splice site of exon 7 2-fold, whereas the strength of the 5 splice site of the exon 7 is not affected. Thus, a decrease in splice site strength is magnified in the context of competing exons. These data suggest that lower levels of exon 7 definition not only reduce intron 6 removal but, more importantly, increase the efficiency of the competing exon 7 skipping pathway. Antisense oligonucleotides were tested to modulate exon 7 inclusion, which contains the authentic translation stop codon. Oligonucleotides directed toward the 3 splice site of exon 8 were shown to alter SMN2 splicing in favor of exon 7 inclusion. These results suggest that antisense oligonucleotides could be used as a therapeutic strategy to counteract the progression of SMA.Proximal spinal muscular atrophy (SMA) 1 is a common human genetic disease that is the leading cause of hereditary infant mortality (1-3). It is characterized by the progressive degeneration of the anterior horn stem cells of the spinal cord with consequent paralysis of the trunk and limbs. Three clinical groups of the disease (I-III) have been described based on the decreasing severity of the symptoms (4). SMA has been linked to deletions or mutations of the survival of motor neuron (SMN) gene, which has been mapped as an inverted repeat to chromosome 5 at 5q13 (4). Homozygous absence of the telomeric copy (SMN1) correlates with development of SMA (5, 6). By contrast, alterations within the centromeric SMN gene (SMN2) do not produce any known phenotype (4). It has been demonstrated that SMN levels produced from the SMN2 locus modify the severity of the disease in a dose-dependent manner (7,8). However, SMN2 alone cannot provide protection from SMA (9 -11).The majority of the SMN transcript consists of 9 exons encoding for a 294-amino acid (38 kDa) gene product. The ubiquitously expressed protein is detected at especially high levels in neuronal cells (7,8). Until recently, it was unclear why only mutations in the telomeric SMN1 mutations result in SMA. A genomic sequence comparison of the two genes revealed that SMN1 and SMN2 encode for the identical protein (12). However, three alternatively spliced transcripts generated with different efficiencies have been described for each locus (4). SMN1 primarily produces the full-length form of SMN, whereas differential splicing of the SMN2 pre-mRNA predominantly produces an isoform lacking exon 7 (SMN⌬7). Comparison of SMN transcripts revealed a direct relationship between SMA and exon 7 skipping. Furthermore, it was demonstrated that SMN⌬7 is unable to efficiently self-assoc...

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“…Two SMN (survival motor neuron) genes typically are present on 5q13: SMN1 and SMN2. Homozygous absence of the telomeric copy, SMN1 (also known as SMNtel), correlates with development of SMA (2)(3)(4)(5). Although several additional genes are located within the SMA region, a number of intragenic SMN1 mutations including frameshifts and point mutations have been identified that conclusively identified SMN1 as the SMA-determining gene (reviewed in ref.…”

mentioning

confidence: 99%

A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy

Lorson

Hahnen

Androphy³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

1,374

1,000

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SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a new SMN1 mutation showed a direct relationship between presence of disease and exon 7 skipping. We have reported previously that the exon-skipped product SMNDelta7 is partially defective for self-association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer. These findings demonstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA retain the SMN2 allele, therapy targeted at preventing exon 7 skipping could modify clinical outcome.

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Prenatal Prediction of Spinal Muscular Atrophy

Cited by 17 publications

References 31 publications

Htra2-β 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 ( SMN2 )

Htra2-β 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 ( SMN2 )

Modulation of Survival Motor Neuron Pre-mRNA Splicing by Inhibition of Alternative 3′ Splice Site Pairing

A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy

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