Splicing Error in E1α Pyruvate Dehydrogenase mRNA Caused by Novel Intronic Mutation Responsible for Lactic Acidosis and Mental Retardation

Miné, Manuèle; Brivet, M.; Touati, Guy; Grabowski, Paula J.; Abitbol, Marc; Marsac, Cécile

doi:10.1074/jbc.m211106200

Cited by 45 publications

(28 citation statements)

References 25 publications

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“…However, we did detect a C / T polymorphism in intron 3 at position 1587 that lies between SNP 20 and SNP 21 and is heterozygous in the female parent, as is SNP 18. Mutations in exon-splicing enhancer (ESE) elements found in introns have been shown to disrupt normal splicing (Kanopka et al 1996;Mine et al 2003). Using an ESE-finding program (http:/ /exon.cshl.edu/ESE/index.html), several ESEs, which were disrupted by haplotype polymorphisms associated with MFA, were detected in intron 3.…”

Section: Resultsmentioning

confidence: 99%

Polymorphisms in Cinnamoyl CoA Reductase (CCR) Are Associated With Variation in Microfibril Angle in Eucalyptus spp.

et al. 2005

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Linkage disequilibrium (LD) mapping using natural populations results in higher resolution of markertrait associations compared to family-based quantitative trait locus (QTL) studies. Depending on the extent of LD, it is possible to identify alleles within candidate genes associated with a trait. Analysis of a natural mutant in Arabidopsis has shown that mutations in cinnamoyl CoA reductase (CCR), a key lignin gene, affect physical properties of the secondary cell wall such as stiffness and strength. Using this gene, we tested whether LD mapping could identify alleles associated with microfibril angle (MFA), a wood quality trait affecting stiffness and strength of wood. We identified 25 common single-nucleotide polymorphism (SNP) markers in the CCR gene in Eucalyptus nitens. Using single-marker and haplotype analyses in 290 trees from a E. nitens natural population, two haplotypes significantly associated with MFA were found. These results were confirmed in two full-sib families of E. nitens and Eucalyptus globulus. In an effort to understand the functional significance of the SNP markers, we sequenced the cDNA clones and identified an alternatively spliced variant from the significant haplotype region. This study demonstrates that LD mapping can be used to identify alleles associated with wood quality traits in natural populations of trees.

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Section: Resultsmentioning

confidence: 99%

Polymorphisms in Cinnamoyl CoA Reductase (CCR) Are Associated With Variation in Microfibril Angle in Eucalyptus spp.

et al. 2005

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“…Mutations affecting these sequences have been shown to lead to exon skipping, because they abrogate or significantly reduce binding of specific SR proteins (11). To test whether some indole derivatives could differentially alter splicing events depending on distinct classes of ESE within the same substrate, we used a chimeric three-exon model substrate (␤glo-3S-PDH) in which sequences of exon 7, intron 7 containing a G to A substitution at ϩ26, and exon 8 of the E1␣ pyruvate dehydrogenase (PDH) gene (29) were inserted downstream of the ␤glo-3S sequences (Fig. 4A).…”

Section: Resultsmentioning

confidence: 99%

Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors

Soret

Bakkour

Maire

et al. 2005

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

111

106

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The prevalence of alternative splicing as a target for alterations leading to human genetic disorders makes it highly relevant for therapy. Here we have used in vitro splicing reactions with different splicing reporter constructs to screen 4,000 chemical compounds for their ability to selectively inhibit spliceosome assembly and splicing. We discovered indole derivatives as potent inhibitors of the splicing reaction. Importantly, compounds of this family specifically inhibit exonic splicing enhancer (ESE)-dependent splicing, because they interact directly and selectively with members of the serine-arginine-rich protein family. Treatment of cells expressing reporter constructs with ESE sequences demonstrated that selected indole derivatives mediate inhibition of ESE usage in vivo and prevent early splicing events required for HIV replication. This discovery opens the exciting possibility of a causal pharmacological treatment of aberrant splicing in human genetic disorders and development of new antiviral therapeutic approaches.splicing correction ͉ exonic splicing enhancer ͉ small chemicals ͉ pathologic splicing R emoval of introns from newly transcribed RNA polymerase II precursors (pre-mRNA) during splicing not only is an essential step for the expression of most genes in higher eukaryotic cells but also constitutes an important mechanism for generation of protein diversity and regulation of gene expression (1, 2). It is estimated that Ͼ70% of human genes are subjected to alternative splicing, and it is not surprising that many point mutations causing human diseases are associated with aberrant splicing (3, 4).Current models of constitutive and a fortiori alternative splicing suggest that splice site recognition is strongly modulated by the interaction of specific exonic and intronic pre-mRNA sequences with at least two classes of nonspliceosomal nuclear RNA-binding proteins: serine-arginine-rich (SR) proteins (5-7) and heterogeneous nuclear ribonucleoproteins (8-10). These proteins interact with spliceosomal components (5-7) and either activate or prevent the use of degenerate splice sites in their vicinity. Thus, binding of SR proteins to exonic splicing enhancers (ESE) through their RNA-recognition motif (RRM) promotes exon definition by recruiting constitutive factors via protein-protein interactions mediated by their arginine-serine-rich (RS) domain and prevents the action of nearby splicing silencers (4, 6, 11).Mutations causing human diseases may affect splice sites as well as regulatory sequences leading to the production of defective proteins (4, 11). Thus, targeting either the mutated sequences or the factors that bind them may prove to be a valuable strategy to correct aberrant splicing. Recently, antisense strategies targeting ESEdependent mechanisms have been used to induce skipping of exons containing nonsense mutations or, conversely, to restore exon inclusion by synthetic exon-specific effectors (bifunctional antisense peptide molecules or tailed antisense oligonucleotides) or spliceosome-mediat...

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“…The third example is an intronic substitution 26 nucleotides downstream from the normal exon 7 splice donor site. This results in activation of a cryptic splice donor site downstream of the mutation and incorporation of 45 nucleotides of intron 7 into the mRNA transcript (Mine, et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

A putative exonic splicing enhancer in exon 7 of thePDHA1 gene affects splicing of adjacent exons

Ridout¹,

Keighley²,

Krywawych³

et al. 2008

Hum. Mutat.

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A nonsense mutation (c.729C>A, Y243X) in exon 7 of the PDHA1 gene in a patient with pyruvate dehydrogenase deficiency results in aberrant splicing of the primary transcript with production of stable mRNAs which lack either both exons 6 and 7 or exon 7 alone. Transfection and expression of genomic constructs covering exons 5 to 8 of the mutant PDHA1 gene reproduced this aberrant splicing in vitro. The same pattern of abnormal splicing was found when a silent mutation was introduced at the same position. Both the nonsense and silent mutations alter a strong consensus site for the binding of SRp40, suggesting that they may interfere with an exonic splicing enhancer in exon 7 of the gene. However, this appears to affect splicing of not only exon 7, but also the adjacent upstream exon. The splice acceptor site of intron 5 has weak homology to the consensus sequence and this may contribute to the combined splicing defect.

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Splicing Error in E1α Pyruvate Dehydrogenase mRNA Caused by Novel Intronic Mutation Responsible for Lactic Acidosis and Mental Retardation

Cited by 45 publications

References 25 publications

Polymorphisms in Cinnamoyl CoA Reductase (CCR) Are Associated With Variation in Microfibril Angle in Eucalyptus spp.

Polymorphisms in Cinnamoyl CoA Reductase (CCR) Are Associated With Variation in Microfibril Angle in Eucalyptus spp.

Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors

A putative exonic splicing enhancer in exon 7 of thePDHA1 gene affects splicing of adjacent exons

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