Comment on: Marchand and Polychronakos (2007) Evaluation of Polymorphic Splicing in the Mechanism of the Association of the Insulin Gene with Diabetes: <i>Diabetes</i> 56:709–713

Rodriguez, Santiago; Gaunt, Tom R.; Vořechovský, Igor; Královičová, Jana; Wood, Peter; Day, Ian N.M.

doi:10.2337/db07-0805

Cited by 4 publications

(4 citation statements)

References 5 publications

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“…odriguez et al (1) are right in pointing out that our findings (2) do not rule out with absolute certainty a role for rs689 in type 1 diabetes through the effects on splicing under conditions not reflected in the tissues we examined. In biological science, absolute certainty is difficult to attain.…”

contrasting

confidence: 57%

Response to Comment on: Marchand and Polychronakos (2007) Evaluation of Polymorphic Splicing in the Mechanism of the Association of the Insulin Gene with Diabetes: Diabetes 56:709–713

Marchand¹,

Polychronakos²

2007

Diabetes

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contrasting

confidence: 57%

Response to Comment on: Marchand and Polychronakos (2007) Evaluation of Polymorphic Splicing in the Mechanism of the Association of the Insulin Gene with Diabetes: Diabetes 56:709–713

Marchand¹,

Polychronakos²

2007

Diabetes

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“…In a study of the human insulin gene ( INS ), we recognised in silico , subsequently confirmed in vitro and in silico [7] , and later in vivo by others [8] , [9] , that polymorphism in a 5′ non-coding intron (separating non-coding exon 1 from coding exon 2) could influence intron retention in the final mRNA. In addition to transcriptional effects, there were major proinsulin expression effects, possibly due to the different 5′ untranslated sequence in the message [10] .…”

Section: Introductionmentioning

confidence: 76%

Genome-Wide Data-Mining of Candidate Human Splice Translational Efficiency Polymorphisms (STEPs) and an Online Database

2010

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BackgroundVariation in pre-mRNA splicing is common and in some cases caused by genetic variants in intronic splicing motifs. Recent studies into the insulin gene (INS) discovered a polymorphism in a 5′ non-coding intron that influences the likelihood of intron retention in the final mRNA, extending the 5′ untranslated region and maintaining protein quality. Retention was also associated with increased insulin levels, suggesting that such variants - splice translational efficiency polymorphisms (STEPs) - may relate to disease phenotypes through differential protein expression. We set out to explore the prevalence of STEPs in the human genome and validate this new category of protein quantitative trait loci (pQTL) using publicly available data.Methodology/Principal FindingsGene transcript and variant data were collected and mined for candidate STEPs in motif regions. Sequences from transcripts containing potential STEPs were analysed for evidence of splice site recognition and an effect in expressed sequence tags (ESTs). 16 publicly released genome-wide association data sets of common diseases were searched for association to candidate polymorphisms with HapMap frequency data. Our study found 3324 candidate STEPs lying in motif sequences of 5′ non-coding introns and further mining revealed 170 with transcript evidence of intron retention. 21 potential STEPs had EST evidence of intron retention or exon extension, as well as population frequency data for comparison.Conclusions/SignificanceResults suggest that the insulin STEP was not a unique example and that many STEPs may occur genome-wide with potentially causal effects in complex disease. An online database of STEPs is freely accessible at http://dbstep.genes.org.uk/.

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“…The A allele of the INS gene restriction fragment length polymorphism Ϫ23HphI leads to retention of intron 1, and the extended mRNAs generate 6-fold more proinsulin in culture supernatants than natural transcripts (22,23 ). This new type of polymorphism has been termed "splicing and translational efficiency polymorphism" (STEP) (24 ).…”

Section: Discussionmentioning

confidence: 99%

Very Low PSA Concentrations and Deletions of the KLK3 Gene

et al. 2013

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BACKGROUND Prostate-specific antigen (PSA), a widely used biomarker for prostate cancer (PCa), is encoded by a kallikrein gene (KLK3, kallikrein-related peptidase 3). Serum PSA concentrations vary in the population, with PCa patients generally showing higher PSA concentrations than control individuals, although a small proportion of individuals in the population display very low PSA concentrations. We hypothesized that very low PSA concentrations might reflect gene-inactivating mutations in KLK3 that lead to abnormally reduced gene expression. METHODS We have sequenced all KLK3 exons and the promoter and searched for gross deletions or duplications in KLK3 in the 30 individuals with the lowest observed PSA concentrations in a sample of approximately 85 000 men from the Prostate Testing for Cancer and Treatment (ProtecT) study. The ProtecT study examines a community-based population of men from across the UK with little prior PSA testing. RESULTS We observed no stop codons or frameshift mutations, but we did find 30 single-base genetic variants, including 3 variants not described previously. These variants included missense variants that could be functionally inactivating and splicing variants. At this stage, however, we cannot confidently conclude whether these variants markedly lower PSA concentration or activity. More importantly, we identified 3 individuals with different large heterozygous deletions that encompass all KLK3 exons. The absence of a functional copy of KLK3 in these individuals is consistent with their reduced serum PSA concentrations. CONCLUSIONS The clinical interpretation of the PSA test for individuals with KLK3 gene inactivation could lead to false-negative PSA findings used for screening, diagnosis, or monitoring of PCa.

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Comment on: Marchand and Polychronakos (2007) Evaluation of Polymorphic Splicing in the Mechanism of the Association of the Insulin Gene with Diabetes: Diabetes 56:709–713

Cited by 4 publications

References 5 publications

Response to Comment on: Marchand and Polychronakos (2007) Evaluation of Polymorphic Splicing in the Mechanism of the Association of the Insulin Gene with Diabetes: Diabetes 56:709–713

Response to Comment on: Marchand and Polychronakos (2007) Evaluation of Polymorphic Splicing in the Mechanism of the Association of the Insulin Gene with Diabetes: Diabetes 56:709–713

Genome-Wide Data-Mining of Candidate Human Splice Translational Efficiency Polymorphisms (STEPs) and an Online Database

Very Low PSA Concentrations and Deletions of the KLK3 Gene

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