Characterization and prediction of alternative splice sites

Wang, Magnus; Marı́n, Antonio

doi:10.1016/j.gene.2005.07.015

Cited by 234 publications

(212 citation statements)

References 36 publications

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“…Neural network predictions of splice sites were performed using NetGene2 (www.cbs.dtu.dk/netgene2/) 25,26 and Alternative Splice Site Predictor (ASSP). 27 …”

Section: Genotypingmentioning

confidence: 99%

Micro-exons of the cardiac myosin binding protein C gene: flanking introns contain a disproportionately large number of hypertrophic cardiomyopathy mutations

et al. 2008

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Hypertrophic cardiomyopathy is primarily caused by mutations in genes encoding cardiac sarcomere proteins. Large screening studies identify mutations in 35-65% of the diagnosed patients and 15-30% of these are discovered within the MYBPC3 gene encoding the cardiac myosin binding protein C. The aim of this study is to determine whether intronic variation flanking the three micro-exons in MYBPC3 is diseasecausing. Two hundred and fifty unrelated patients with hypertrophic cardiomyopathy were genotyped in MYBPC3, using automated single-strand conformation polymorphism, and sequenced for confirmation. Mutations located in the flanking introns of the MYBPC3 micro-exons were examined using in silico methods. Ectopic expression of mRNA in blood leukocytes in the respective patients was examined using reverse transcription-PCR. A total of seven mutations were discovered in the introns flanking the two micro-exons 10 and 14, but none were found in introns flanking exon 11. Functional studies together with co-segregation analysis indicate that four mutations are associated with HCM, in the respective patients. All four mutations result in premature termination codons, which suggests that haploinsufficiency is a pathogenic mechanism of this type of mutation. It is demonstrated that the use of in silico methods together with RNA studies on peripheral blood leukocytes is a useful tool to evaluate the potential effects of mutations on pre-mRNA splicing.

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“…Neural network predictions of splice sites were performed using NetGene2 (www.cbs.dtu.dk/netgene2/) 25,26 and Alternative Splice Site Predictor (ASSP). 27 …”

Section: Genotypingmentioning

confidence: 99%

Micro-exons of the cardiac myosin binding protein C gene: flanking introns contain a disproportionately large number of hypertrophic cardiomyopathy mutations

et al. 2008

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“…As SNP 18 is a synonymous mutation and SNPs 19 and 20 are located within introns 2 and 4, respectively, we found no obvious functional implications. Neither splice sites 68 nor transcription factor binding sites 69 are affected and the variants do not introduce cryptic splice sites. Due to the fact that the functional variant might be in close LD with one of the haplotype SNPs, we had a further look at a total of 153 SNPs found in dbSNP (http://www.ncbi.nlm.…”

Section: Discussionmentioning

confidence: 97%

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

et al. 2007

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Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5 0 region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P = 0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n = 3) tested blocks (P = 0.0048); (3) within block two we detected a nominal P = 0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P < 0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p.

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“…The potential effects on splicing of the detected intronic and silent changes were predicted in silico by computational methods by using NetGene2, Alternative Splice Site Predictor (ASSP), and SpliceScan programs (31)(32)(33)(34).…”

Section: Methodsmentioning

confidence: 99%

Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations

Georgitsi

Raitila

Karhu

et al. 2007

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

170

154

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Pituitary adenomas are common neoplasms of the anterior pituitary gland. Germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause pituitary adenoma predisposition (PAP), a recent discovery based on genetic studies in Northern Finland. In this population, a founder mutation explained a significant proportion of all acromegaly cases. Typically, PAP patients were of a young age at diagnosis but did not display a strong family history of pituitary adenomas. To evaluate the role of AIP in pituitary adenoma susceptibility in other populations and to gain insight into patient selection for molecular screening of the condition, we investigated the possible contribution of AIP mutations in pituitary tumorigenesis in patients from Europe and the United States. A total of 460 patients were investigated by AIP sequencing: young acromegaly patients, unselected acromegaly patients, unselected pituitary adenoma patients, and endocrine neoplasia-predisposition patients who were negative for MEN1 mutations. Nine AIP mutations were identified. Because many of the patients displayed no family history of pituitary adenomas, detection of the condition appears challenging. Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 adenomas: 12 AIP mutation-positive versus 38 mutation-negative pituitary tumors. AIP IHC staining levels proved to be a useful predictor of AIP status, with 75% sensitivity and 95% specificity for germ-line mutations. AIP contributes to PAP in all studied populations. AIP IHC, followed by genetic counseling and possible AIP mutation analysis in IHC-negative cases, a procedure similar to the diagnostics of the Lynch syndrome, appears feasible in identification of PAP.immunohistochemistry ͉ growth hormone/prolacting-secreting adenomas ͉ acromegaly

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Characterization and prediction of alternative splice sites

Cited by 234 publications

References 36 publications

Micro-exons of the cardiac myosin binding protein C gene: flanking introns contain a disproportionately large number of hypertrophic cardiomyopathy mutations

Micro-exons of the cardiac myosin binding protein C gene: flanking introns contain a disproportionately large number of hypertrophic cardiomyopathy mutations

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations

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