Not all pathogenic mutations are pathogenic: KCNH2 mutations in two sisters with tetralogy of Fallot

Bhuiyan, Zahurul A.; Alswaid, Abdulrahman; Belfiore, Marco; Al-Ghamdi, Saleh; Liang, Juno; Schlaepffer, Jürg

doi:10.1016/j.ijcard.2013.12.242

Cited by 5 publications

(5 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the KCNH2 mutation in the fetus was inherited from her mother, who had no obvious cardiac phenotype. Similar to a previous study ( Bhuiyan et al, 2014 ), two sisters in a close relative married family were found to carry the KCNH2 mutation, which was also inherited from their normal mother, which suggests incomplete penetrance of KCNH2 , although it cannot be ruled out that the phenotype may appear in her mother in the future. Therefore, our study indicated that the additional variant in the KCNH2 gene identified in the fetus may be responsible for fetal ultrasound anomalies, rather than the 2q14.2 duplication.…”

Section: Discussionsupporting

confidence: 79%

“…The main mutation types in LQT2 are nonsense mutation and missense mutation, with more than half of them being nonsense mutations and predict to result in haploinsufficiency through nonsense-mediated RNA decay ( Ono et al, 2020 ). At present, no specific forms of congenital heart defects (CHD) have been reported to associate with LQT2, while several cases with KCNH2 mutations showed coexistence of CHD ( Bhuiyan et al, 2014 ; Ebrahim et al, 2017 ; Song et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Case Report: Prenatal Whole-Exome Sequencing Identified a Novel Nonsense Mutation of the KCNH2 Gene in a Fetus With Familial 2q14.2 Duplication

Zhuang¹,

Chen

Wang³

et al. 2022

Front. Genet.

View full text Add to dashboard Cite

Background: Pathogenic mutations in the KCNH2 gene were associated with long QT syndrome 2 (LQT2), which typically manifest in a prolonged QT interval and may lead to recurrent syncopes, seizure, or sudden death. Limited reports indicated that the KCNH2 mutations would result in LQT2 combined with tetralogy of fallot. Our goal was to present an additional case of LQT2 combined with the tetralogy of fallot in a fetus with a novel KCNH2 mutation.Case presentation: Enrolled in this study was a 23-year-old pregnant woman from Quanzhou Fujian province, China. In her pregnancy, fetal ultrasound anomalies were identified, including tetralogy of fallot, coronary sinus enlargement, and persistent left superior vena cava. No chromosomal abnormality was detected by fetal karyotype analysis. However, 238.1-kb duplication in the 2q14.2 region containing the GLI2 gene was observed in the fetus by chromosomal array analysis, which was inherited from the mother with normal clinical features and interpreted as a variant of uncertain significance (VOUS). Furthermore, whole-exome sequencing (WES) detection identified a novel nonsense c.1907C > G (p.S636*) mutation in the KCNH2 gene in the fetus, and it was classified as a likely pathogenic variant, according to the ACMG guidelines. Parental verification analysis indicated that c.1907C > G (p.S636*) mutation was inherited from the mother.Conclusion: In this study, we believe that 2q14.2 duplication may not be the reason for fetal heart defects; moreover, we described an additional case with KCNH2 gene mutation, which may lead to LQTS and be associated with congenital heart defects. In addition, our study further confirms the application value of the WES technology in prenatal genetic etiology diagnosis of fetuses with structural anomalies and unexplained structural variants.

show abstract

Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Case Report: Prenatal Whole-Exome Sequencing Identified a Novel Nonsense Mutation of the KCNH2 Gene in a Fetus With Familial 2q14.2 Duplication

Zhuang¹,

Chen

Wang³

et al. 2022

Front. Genet.

View full text Add to dashboard Cite

show abstract

“…KCNH2 transcripts are observed at the earliest stages of mouse cardiac development ( 67 ) and have even been reported in developing mouse embryos prior to implantation ( 68 ). In fact, loss-of-function KCNH2 variants have been identified in cases of tetralogy de Fallot ( 69 , 70 ), which suggests that hERG1 may also contribute to cardiomorphogenesis in humans as well. Evolutionary analysis also demonstrates an ancestral origin for ERG channels that predates the divergence of cnidarians and bilaterians ( 71 ).…”

Section: Discussionmentioning

confidence: 99%

KCNH2 encodes a nuclear-targeted polypeptide that mediates hERG1 channel gating and expression

Jain

Stack

Ghodrati

et al. 2023

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

View full text Add to dashboard Cite

KCNH2 encodes hERG1, the voltage-gated potassium channel that conducts the rapid delayed rectifier potassium current (I Kr ) in human cardiac tissue. hERG1 is one of the first channels expressed during early cardiac development, and its dysfunction is associated with intrauterine fetal death, sudden infant death syndrome, cardiac arrhythmia, and sudden cardiac death. Here, we identified a hERG1 polypeptide (hERG1 NP ) that is targeted to the nuclei of immature cardiac cells, including human stem cell-derived cardiomyocytes (hiPSC-CMs) and neonatal rat cardiomyocytes. The nuclear hERG1 NP immunofluorescent signal is diminished in matured hiPSC-CMs and absent from adult rat cardiomyocytes. Antibodies targeting distinct hERG1 channel epitopes demonstrated that the hERG1 NP signal maps to the hERG1 distal C-terminal domain. KCNH2 deletion using CRISPR simultaneously abolished I Kr and the hERG1 NP signal in hiPSC-CMs. We then identified a putative nuclear localization sequence (NLS) within the distal hERG1 C-terminus, 883-RQRKRKLSFR-892. Interestingly, the distal C-terminal domain was targeted almost exclusively to the nuclei when overexpressed HEK293 cells. Conversely, deleting the NLS from the distal peptide abolished nuclear targeting. Similarly, blocking α or β1 karyopherin activity diminished nuclear targeting. Finally, overexpressing the putative hERG1 NP peptide in the nuclei of HEK cells significantly reduced hERG1a current density, compared to cells expressing the NLS-deficient hERG1 NP or GFP. These data identify a developmentally regulated polypeptide encoded by KCNH2 , hERG1 NP , whose presence in the nucleus indirectly modulates hERG1 current magnitude and kinetics.

show abstract

“…KCNH2 transcripts are observed at the earliest stages of mouse cardiac development (67), and have even been reported in developing mouse embryos prior to implantation (68). In fact, loss-of-function KCNH2 variants have been identified in cases of tetralogy de Fallot (69, 70), which suggests that hERG1 may also contribute to cardiomorphogenesis in humans as well. Evolutionary analysis also demonstrates an ancestral origin for ERG channels that predates the divergence of cnidarians and bilaterians (71).…”

Section: Discussionmentioning

confidence: 99%

KCNH2encodes a nuclear-targeted polypeptide that mediates hERG1 channel gating and expression

Jain

Stack

Ghodrati

et al. 2022

Preprint

View full text Add to dashboard Cite

KCNH2 encodes hERG1, the voltage-gated potassium channel that conducts the rapid delayed rectifier potassium current (IKr) in human cardiac tissue. hERG1 is one of the first channels expressed during early cardiac development, and its dysfunction is associated with intrauterine fetal death, sudden infant death syndrome, cardiac arrhythmia, and sudden cardiac death. Here, we identified a novel hERG1 polypeptide (hERG1NP) that is targeted to the nuclei of immature cardiac cells, including hiPSC-CMs and neonatal rat cardiomyocytes. The nuclear hERG1NP immunofluorescent signal is diminished in matured hiPSC-CMs and absent from adult rat cardiomyocytes. Antibodies targeting distinct hERG1 channel epitopes demonstrated that the hERG1NP signal maps to the hERG1 distal C-terminal domain. KCNH2 deletion using CRISPR simultaneously abolished IKr and the hERG1NP signal in hiPSC-CMs. We then identified a putative nuclear localization sequence (NLS) within the distal hERG1 C-terminus, 883-RQRKRKLSFR-892. Interestingly, the distal C-terminal domain was targeted almost exclusively to the nuclei when overexpressed HEK293 cells. Conversely, deleting the NLS from the distal peptide abolished nuclear targeting. Similarly, blocking [alpha]; or [beta]1 karyopherin activity diminished nuclear targeting. Finally, overexpressing the putative hERG1NP peptide in the nuclei of HEK cells significantly reduced hERG1a current density, compared to cells expressing the NLS-deficient hERG1NP or GFP. These data identify a developmentally regulated polypeptide encoded by KCNH2, hERG1NP, whose presence in the nucleus indirectly modulates hERG1 current magnitude and kinetics.

show abstract

Not all pathogenic mutations are pathogenic: KCNH2 mutations in two sisters with tetralogy of Fallot

Cited by 5 publications

References 8 publications

Case Report: Prenatal Whole-Exome Sequencing Identified a Novel Nonsense Mutation of the KCNH2 Gene in a Fetus With Familial 2q14.2 Duplication

Case Report: Prenatal Whole-Exome Sequencing Identified a Novel Nonsense Mutation of the KCNH2 Gene in a Fetus With Familial 2q14.2 Duplication

KCNH2 encodes a nuclear-targeted polypeptide that mediates hERG1 channel gating and expression

KCNH2encodes a nuclear-targeted polypeptide that mediates hERG1 channel gating and expression

Contact Info

Product

Resources

About