Novel compound heterozygous mutations T2C and 1149insT in the KCNQ1 gene cause Jervell and Lange-Nielsen syndrome

  • Authors:
    • Rong-Rong Wang
    • Ning Li
    • Yin-Hui Zhang
    • Lin-Lin Wang
    • Si-Yong Teng
    • Jie-Lin Pu
  • View Affiliations

  • Published online on: March 4, 2011     https://doi.org/10.3892/ijmm.2011.642
  • Pages: 41-46
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Abstract

Mutations in the KCNQ1 gene account for more than 90% of the individuals with Jervell and Lange-Nielsen syndrome (JLNS). In this study, we identified and characterized two novel KCNQ1 mutations that caused JLNS. A 6-year-old deaf girl suffering from recurrent syncope had a documented electrocardiogram with polymorphic ventricular fibrillation since the age of 4 years. The baseline electrocardiogram showed a significantly prolonged corrected QT interval (524 msec). Genetic analysis revealed that the proband carried two heterozygous mutations of T2C and 1149insT in the KCNQ1 gene on separate alleles. Patch-clamp analysis demonstrated that the T2C mutation resulted in significant reduction in the slowly activated delayed rectifier current (IKs). Furthermore, western blot analysis and confocal imaging revealed that the T2C mutation produced a truncated protein with trafficking defects. In contrast, the 1149insT mutation failed to generate any measurable current, consistent with no protein expression in both the cell membrane and cytoplasm. Moreover, co-expression of the T2C and 1149insT mutations significantly reduced the peak tail current density to 8.27% of the wild-type (WT) current value, while co-transfected WT channels with either T2C or 1149insT mutant channels produced comparable current and channel kinetics to that of WT channels. Our study demonstrates that the compound heterozygous mutations T2C and 1149insT cause the ‘loss-of-function’ of the IKs that may account for the clinical phenotype of the proband. Multiple mechanisms have been involved in the pathogenesis of ‘loss-of-function’ of IKs.

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July 2011
Volume 28 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Wang R, Li N, Zhang Y, Wang L, Teng S and Pu J: Novel compound heterozygous mutations T2C and 1149insT in the KCNQ1 gene cause Jervell and Lange-Nielsen syndrome. Int J Mol Med 28: 41-46, 2011
APA
Wang, R., Li, N., Zhang, Y., Wang, L., Teng, S., & Pu, J. (2011). Novel compound heterozygous mutations T2C and 1149insT in the KCNQ1 gene cause Jervell and Lange-Nielsen syndrome. International Journal of Molecular Medicine, 28, 41-46. https://doi.org/10.3892/ijmm.2011.642
MLA
Wang, R., Li, N., Zhang, Y., Wang, L., Teng, S., Pu, J."Novel compound heterozygous mutations T2C and 1149insT in the KCNQ1 gene cause Jervell and Lange-Nielsen syndrome". International Journal of Molecular Medicine 28.1 (2011): 41-46.
Chicago
Wang, R., Li, N., Zhang, Y., Wang, L., Teng, S., Pu, J."Novel compound heterozygous mutations T2C and 1149insT in the KCNQ1 gene cause Jervell and Lange-Nielsen syndrome". International Journal of Molecular Medicine 28, no. 1 (2011): 41-46. https://doi.org/10.3892/ijmm.2011.642