Prediction of single‐nucleotide substitutions that result in exon skipping: identification of a splicing silencer in<i>BRCA1</i>exon 6

Raponi, Michela; Královičová, Jana; Copson, Ellen; Divina, Petr; Eccles, Diana; Johnson, Peter; Baralle, Diana; Vořechovský, Igor

doi:10.1002/humu.21458

Cited by 129 publications

(107 citation statements)

References 71 publications

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“…Indeed, various silent mutations have been described to be involved in BRCA1 gene expression, such as allelic imbalance (Sharp et al, 2004) or exon skipping (Raponi et al, 2011). The T327T variant might play a role in exon skipping, as suggested by Anczukow et al (2008), since the normal and mutated forms differ in their respective prevalence of exon skipping (application of EX-SKIP, freely available at http://www.…”

Section: Analysis Of the Exon 11b Sequencementioning

confidence: 99%

Specific BRCA1 gene variations amongst young Moroccan breast cancer patients

et al. 2014

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ABSTRACT. Germline mutations in the BRCA1 gene are known predictive markers for the development of hereditary breast cancer. Nevertheless, no comprehensive study has been performed targeting the presence and relevance of BRCA1 mutations in Moroccan breast cancer patients. We here present an analysis of BRCA1 gene regions (exon 2 and exon 11a/b) of 50 female Moroccan breast cancer patients with early disease onset (≤40 years) or familial disease backgrounds. Results showed that no mutation was present in either exon 2 or exon 11a of the BRCA1 gene in any of the 50 patients analysed. However, in exon 11b, a mutation generated by a nucleotide exchange was detected in 8% of patients, most of whom were young women (≤40). This mutation leads to substitution of the amino acid glutamine by an arginine at position 356 of the polypeptide sequence (Q356R). Although this mutation was previously characterised at a lower frequency in western populations, our study is the first to describe it in a young Moroccan population. Furthermore, another mutation was detected with a high frequency (4%) on exon 11b of the BRCA1 gene in exclusively young patients (≤40). This mutation was silent, encoding the same threonine residue at position 327 (T327T) as the wild type. The present study is the first to describe this mutation as well, particularly in a young Moroccan population. Analysis of a larger population is required in order to highlight the relevance of the Q356R and T327T mutations in young Moroccan breast cancer patients.

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Section: Analysis Of the Exon 11b Sequencementioning

confidence: 99%

Specific BRCA1 gene variations amongst young Moroccan breast cancer patients

et al. 2014

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“…Patients from the nonconsanguineous family NCR61 (Table 1 and Figure 1, B-E) were found to be compound heterozygous for a frameshift mutation (p.Arg278Glyfs*17) and a missense mutation (p.Glu132Gly) not predicted to be deleterious by the PolyPhen (http://genetics.bwh.harvard.edu/pph2/) and SIFT (http:// sift.jcvi.org/) prediction tools, but predicted to induce skipping of exon 5 due to the introduction of additional exon splicing silencer elements (EX-SKIP, http://ex-skip.img.cas.cz) (8). Fibroblasts of patient NCR61-1 had almost no SGPL1 protein detectable by Western blot at the predicted size (Supplemental Figure 4A).…”

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confidence: 99%

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Lovric¹,

Gonçalves²,

Gee³

et al. 2017

Journal of Clinical Investigation

181

174

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Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of diseaseassociated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.

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“…Mutations within the ESEs exert an inhibitory effect on the binding of SRSFs following a failure of correct splicing due to exon skipping in mature mRNA. [8][9][10] This "exon skipping due to ESE disruption" has been well-investigated in certain neurologic and inherited pediatric disorders. 11,12 A novel therapeutic approach that normalizes aberrant splicing by the administration of specific reagents have already been applied to animal models.…”

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confidence: 99%

Exonic Mutations in the SLC12A3 Gene Cause Exon Skipping and Premature Termination in Gitelman Syndrome

Takeuchi

Mishima

Shima

et al. 2015

Journal of the American Society of Nephrology

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A variety of genetic backgrounds cause the loss of function of thiazide-sensitive sodium chloride cotransporter, encoded by SLC12A3, responsible for the phenotypes in Gitelman syndrome. Recently, the phenomenon of exon skipping, in which exonic mutations result in abnormal splicing, has been associated with various diseases. Specifically, mutations in exonic splicing enhancer (ESE) sequences can promote exon skipping. Here, we used a bioinformatics program to analyze 88 missense mutations in the SLC12A3 gene and identify candidate mutations that may induce exon skipping. The three candidate mutations that reduced ESE scores the most were further investigated by minigene assay, and two (p.A356V and p.M672I) caused abnormal splicing in vitro. Furthermore, we identified the p.M672I (c.2016G.A) mutation in a patient with Gitelman syndrome and found that this single nucleotide mutation causes exclusion of exon 16 in the SLC12A3 mRNA transcript. Functional analyses revealed that the protein encoded by the aberrant SLC12A3 transcript does not transport sodium. These results suggest that aberrant exon skipping is one previously unrecognized mechanism by which missense mutations in SLC12A3 can lead to Gitelman syndrome.

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Prediction of single‐nucleotide substitutions that result in exon skipping: identification of a splicing silencer inBRCA1exon 6

Cited by 129 publications

References 71 publications

Specific BRCA1 gene variations amongst young Moroccan breast cancer patients

Specific BRCA1 gene variations amongst young Moroccan breast cancer patients

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Exonic Mutations in the SLC12A3 Gene Cause Exon Skipping and Premature Termination in Gitelman Syndrome

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