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Protective effect of KCNH2 single nucleotide polymorphism K897T in LQTS families and identification of novel KCNQ1 and KCNH2 mutations.

Zhang X, Chen S, Zhang L, Liu M, Redfearn S, Bryant RM, Oberti C, Vincent GM, Wang QK - BMC Med. Genet. (2008)

Bottom Line: Notably, we have found that SNP K897T interacts with mutation A490T in cis orientation.Our family-based approach provides support that KCNH2 SNP K897T confers a protective effect on LQTS patients.Our study is the first to investigate the effect of SNP K897T on another KCNH2 mutation located in cis orientation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China. zhangx3@ccf.org

ABSTRACT

Background: KCNQ1 and KCNH2 are the two most common potassium channel genes causing long QT syndrome (LQTS), an inherited cardiac arrhythmia featured by QT prolongation and increased risks of developing torsade de pointes and sudden death. To investigate the disease expressivity, this study aimed to identify mutations and common variants that can modify LQTS phenotype.

Methods: In this study, a cohort of 112 LQTS families were investigated. Among them two large LQTS families linkage analysis with markers spanning known LQTS genes was carried out to identify the specific gene for mutational analysis. All exons and exon-intron boundaries of KCNH2 and KCNQ1 were sequenced for mutational analysis.

Results: LQTS-associated mutations were identified in eight of 112 families. Two novel mutations, L187P in KCNQ1 and 2020insAG in KCNH2, were identified. Furthermore, in another LQTS family we found that KCNH2 mutation A490T co-segregated with a common SNP K897T in KCNH2. KCNH2 SNP K897T was reported to exert a modifying effect on QTc, but it remains controversial whether it confers a risk or protective effect. Notably, we have found that SNP K897T interacts with mutation A490T in cis orientation. Seven carriers for A490T and the minor allele T of SNP K897T showed shorter QTc and fewer symptoms than carriers with A490T or A490P (P < 0.0001).

Conclusion: Our family-based approach provides support that KCNH2 SNP K897T confers a protective effect on LQTS patients. Our study is the first to investigate the effect of SNP K897T on another KCNH2 mutation located in cis orientation. Together, our results expand the mutational and clinical spectrum of LQTS and provide insights into the factors that determine QT prolongation associated with increased risk of ventricular tachycardia and sudden death.

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Related in: MedlinePlus

Identification of a novel mutation in KCNH2, 2020insAG, in family QW258. Top, pedigree structure; Middle, DNA sequence for the patient using the forward primer; Bottom, DNA sequence for the patient using the reverse primer.
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Figure 4: Identification of a novel mutation in KCNH2, 2020insAG, in family QW258. Top, pedigree structure; Middle, DNA sequence for the patient using the forward primer; Bottom, DNA sequence for the patient using the reverse primer.

Mentions: One novel mutation, a 2-bp insertion 2020insAG, was identified in KCNH2 in family QW258 with LQTS (Fig. 4). The mutation was neither present in three normal family members nor 200 controls. The proband in the family was a 75-year-old female with a prolonged QTc of 0.596–0.687 s and left bundle branch block (QRS = 0.122 s). The patient developed a long run of polymorphic VT at the age of 75 years, which was cardioverted. She also developed two syncopal episodes at the age of 67 and 75 years, and a transient ischemic attack at the age of 63. Telemetry Holter ECG monitoring identified frequent multiform ventricular ectopic beats with occasional supraventricular ectopy, no bradycardia, and 173 runs of polymorphic VT. Echocardiography showed normal left and right ventricles, ejection fraction of 40% and abnormal left ventricular relaxation (stage I diastolic dysfunction). EEG, neurological and hearing tests, and troponin T and creatine kinase-MB levels (0.01 ng/ml and 4.8 ng/ml, respectively) were normal. Cardiac catheterization showed mild luminal irregularities without obstructing lesions, and mild global systolic left ventricular dysfunction consistent with hypertensive cardiomyopathy.


Protective effect of KCNH2 single nucleotide polymorphism K897T in LQTS families and identification of novel KCNQ1 and KCNH2 mutations.

Zhang X, Chen S, Zhang L, Liu M, Redfearn S, Bryant RM, Oberti C, Vincent GM, Wang QK - BMC Med. Genet. (2008)

Identification of a novel mutation in KCNH2, 2020insAG, in family QW258. Top, pedigree structure; Middle, DNA sequence for the patient using the forward primer; Bottom, DNA sequence for the patient using the reverse primer.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2570672&req=5

Figure 4: Identification of a novel mutation in KCNH2, 2020insAG, in family QW258. Top, pedigree structure; Middle, DNA sequence for the patient using the forward primer; Bottom, DNA sequence for the patient using the reverse primer.
Mentions: One novel mutation, a 2-bp insertion 2020insAG, was identified in KCNH2 in family QW258 with LQTS (Fig. 4). The mutation was neither present in three normal family members nor 200 controls. The proband in the family was a 75-year-old female with a prolonged QTc of 0.596–0.687 s and left bundle branch block (QRS = 0.122 s). The patient developed a long run of polymorphic VT at the age of 75 years, which was cardioverted. She also developed two syncopal episodes at the age of 67 and 75 years, and a transient ischemic attack at the age of 63. Telemetry Holter ECG monitoring identified frequent multiform ventricular ectopic beats with occasional supraventricular ectopy, no bradycardia, and 173 runs of polymorphic VT. Echocardiography showed normal left and right ventricles, ejection fraction of 40% and abnormal left ventricular relaxation (stage I diastolic dysfunction). EEG, neurological and hearing tests, and troponin T and creatine kinase-MB levels (0.01 ng/ml and 4.8 ng/ml, respectively) were normal. Cardiac catheterization showed mild luminal irregularities without obstructing lesions, and mild global systolic left ventricular dysfunction consistent with hypertensive cardiomyopathy.

Bottom Line: Notably, we have found that SNP K897T interacts with mutation A490T in cis orientation.Our family-based approach provides support that KCNH2 SNP K897T confers a protective effect on LQTS patients.Our study is the first to investigate the effect of SNP K897T on another KCNH2 mutation located in cis orientation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China. zhangx3@ccf.org

ABSTRACT

Background: KCNQ1 and KCNH2 are the two most common potassium channel genes causing long QT syndrome (LQTS), an inherited cardiac arrhythmia featured by QT prolongation and increased risks of developing torsade de pointes and sudden death. To investigate the disease expressivity, this study aimed to identify mutations and common variants that can modify LQTS phenotype.

Methods: In this study, a cohort of 112 LQTS families were investigated. Among them two large LQTS families linkage analysis with markers spanning known LQTS genes was carried out to identify the specific gene for mutational analysis. All exons and exon-intron boundaries of KCNH2 and KCNQ1 were sequenced for mutational analysis.

Results: LQTS-associated mutations were identified in eight of 112 families. Two novel mutations, L187P in KCNQ1 and 2020insAG in KCNH2, were identified. Furthermore, in another LQTS family we found that KCNH2 mutation A490T co-segregated with a common SNP K897T in KCNH2. KCNH2 SNP K897T was reported to exert a modifying effect on QTc, but it remains controversial whether it confers a risk or protective effect. Notably, we have found that SNP K897T interacts with mutation A490T in cis orientation. Seven carriers for A490T and the minor allele T of SNP K897T showed shorter QTc and fewer symptoms than carriers with A490T or A490P (P < 0.0001).

Conclusion: Our family-based approach provides support that KCNH2 SNP K897T confers a protective effect on LQTS patients. Our study is the first to investigate the effect of SNP K897T on another KCNH2 mutation located in cis orientation. Together, our results expand the mutational and clinical spectrum of LQTS and provide insights into the factors that determine QT prolongation associated with increased risk of ventricular tachycardia and sudden death.

Show MeSH
Related in: MedlinePlus