کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1905117 1534690 2011 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Identification and functional characterization of KCNQ1 mutations around the exon 7–intron 7 junction affecting the splicing process
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی سالمندی
پیش نمایش صفحه اول مقاله
Identification and functional characterization of KCNQ1 mutations around the exon 7–intron 7 junction affecting the splicing process
چکیده انگلیسی

Background. KCNQ1 gene encodes the delayed rectifier K+ channel in cardiac muscle, and its mutations cause long QT syndrome type 1 (LQT1). Especially exercise-related cardiac events predominate in LQT1. We previously reported that a KCNQ1 splicing mutation displays LQT1 phenotypes. Methods and results. We identified novel mutation at the third base of intron 7 (IVS7 + 3A > G) in exercise-induced LQT1 patients. Minigene assay in COS7 cells and RT-PCR analysis of patients' lymphocytes demonstrated the presence of exon 7-deficient mRNA in IVS7 + 3A > G, as well as c.1032G > A, but not in c.1022C > T. Real-time RT-PCR demonstrated that both IVS7 + 3A > G and c.1032G > A carrier expressed significant amounts of exon-skipping mRNAs (18.8% and 44.8% of total KCNQ1 mRNA). Current recordings from Xenopus oocytes injected cRNA by simulating its ratios of exon skipping displayed a significant reduction in currents to 64.8 ± 4.5% for IVS7 + 3A > G and to 41.4 ± 9.5% for c.1032G > A carrier, respectively, compared to the condition without splicing error. Computer simulation incorporating these quantitative results revealed the pronounced QT prolongation under beta-adrenergic stimulation in IVS7 + 3A > G carrier model. Conclusion. Here we report a novel splicing mutation IVS7 + 3A > G, identified in a family with mild form LQT1 phenotypes, and examined functional outcome in comparison with three other variants around the exon 7–intron 7 junction. In addition to c.1032G > A mutation, IVS7 + 3A > G generates exon-skipping mRNAs, and thereby causing LQT1 phenotype. The severity of clinical phenotypes appeared to differ between the two splicing-related mutations and to result from the amount of resultant mRNAs and their functional consequences.


► A novel KCNQ1 splicing mutation IVS7 + 3A > G generates exon-skipping mRNAs.
► In addition to c.1032G > A mutation, novel IVS7 + 3A > G mutation causes LQT1 phenotype.
► The severity of clinical phenotypes appeared to differ between the two mutations.
► The amount of exon-skipping mRNAs may determine the clinical severity of the disease.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1812, Issue 11, November 2011, Pages 1452–1459
نویسندگان
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