Listening to silence and understanding nonsense: exonic mutations that affect splicing

Cartegni, Luca; Chew, Shern L.; Krainer, Adrian R.

doi:10.1038/nrg775

Cited by 1,940 publications

(1,787 citation statements)

References 136 publications

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“…It is possible that changes happening early on in life may set the scene for future longevity, which is an interesting concept given that several genes such as Foxo1, known to be associated with extended lifespan, are developmental genes (Lunetta et al ., 2007). It is very difficult to predict what the consequence of these changes will be to the overall level or pattern of splicing in long‐lived mice or humans, since splice site choice at any given exon: intron junction is determined by the balance of activators and repressors, and that this balance is individually determined for each splice site in each gene (Cartegni et al ., 2002). However, diminished splicing factor expression may be beneficial in younger animals, since both SRSF and hnRNP splicing factors are known to have oncogenic features (Gautrey et al ., 2015; Goncalves & Jordan, 2015; Guo et al ., 2015).…”

Section: Discussionmentioning

confidence: 99%

Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans

Lee¹,

Pilling

Emond³

et al. 2016

Aging Cell

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SummaryDysregulation of splicing factor expression and altered alternative splicing are associated with aging in humans and other species, and also with replicative senescence in cultured cells. Here, we assess whether expression changes of key splicing regulator genes and consequent effects on alternative splicing are also associated with strain longevity in old and young mice, across 6 different mouse strains with varying lifespan (A/J, NOD.B10Sn‐H2b/J, PWD.Phj, 129S1/SvlmJ, C57BL/6J and WSB/EiJ). Splicing factor expression and changes to alternative splicing were associated with strain lifespan in spleen and to a lesser extent in muscle. These changes mainly involved hnRNP splicing inhibitor transcripts with most changes more marked in spleens of young animals from long‐lived strains. Changes in spleen isoform expression were suggestive of reduced cellular senescence and retained cellular proliferative capacity in long‐lived strains. Changes in muscle isoform expression were consistent with reduced pro‐inflammatory signalling in longer‐lived strains. Two splicing regulators, HNRNPA1 and HNRNPA2B1, were also associated with parental longevity in humans, in the InCHIANTI aging study. Splicing factors may represent a driver, mediator or early marker of lifespan in mouse, as expression differences were present in the young animals of long‐lived strains. Changes to alternative splicing patterns of key senescence genes in spleen and key remodelling genes in muscle suggest that correct regulation of alternative splicing may enhance lifespan in mice. Expression of some splicing factors in humans was also associated with parental longevity, suggesting that splicing regulation may also influence lifespan in humans.

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Section: Discussionmentioning

confidence: 99%

Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans

Lee¹,

Pilling

Emond³

et al. 2016

Aging Cell

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“…21 Genetic variations, which cause aberrant splicing, may represent up to 50% of all the deleterious mutations. 30 Depending on tissue localization and/or stage of development, pre-mRNA transcripts may be differentially spliced. We showed that the BRCA2 c.7802A4G variant detected in this study produced 50% of transcripts harbouring a premature stop codon (r.7802_7805delauag) and 50% of transcripts with a p.Tyr2601Cys mutation.…”

Section: Discussionmentioning

confidence: 99%

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

et al. 2013

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Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A4G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A4G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A4G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.

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“…(2) The silent codon214AC C/T polymorphism in exon 7 by itself might lead to the observed phenotypic variability by influencing exonic splicing accuracy or efficiency. The phenomenon of exonic splicing skipping is known from other diseases, such as the neuromuscular disease, Spinal muscular atrophy, as reviewed in Cartegni et al 39 However, the methods for predicting exonic splicing enhancers are still under development. Our results also need to be confirmed in another cohort, as our sample size is relatively small.…”

Section: Discussionmentioning

confidence: 99%

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

et al. 2005

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Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC C/T as well as the FASÀ670G4A 0 -codon214 AC C/T 0 haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the haplotype. The presence of FASÀ670G, which affects STAT1 binding, leads to the highest activity. FASLÀ844C activity is modified by the cis acting À478A and, hence, the haplotype and not the individual variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE.

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Listening to silence and understanding nonsense: exonic mutations that affect splicing

Cited by 1,940 publications

References 136 publications

Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans

Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

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