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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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Identification and co-segregation of KCNH2 mutation A490T and SNP K897T in family QW2648 and with LQTS. (A). Pedigree structure of family QW2648. All the affected individuals carry double variants, K897T and A490T of KCNH2 on the same chromosome (in cis orientation). (B, C). DNA sequence analysis for the proband in family QW2648. A heterozygous G→A transition at nucleotide 1468 of KCNH2, which results in a substitution of alanine by threonine (A490T) (B). DNA sequence for KCNH2 SNP K897T is shown in (C). (D) Comparison of mean QTc for carriers with KCNH2 mutation A490T, A490P, and both A490T and SNP K897T.
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Figure 1: Identification and co-segregation of KCNH2 mutation A490T and SNP K897T in family QW2648 and with LQTS. (A). Pedigree structure of family QW2648. All the affected individuals carry double variants, K897T and A490T of KCNH2 on the same chromosome (in cis orientation). (B, C). DNA sequence analysis for the proband in family QW2648. A heterozygous G→A transition at nucleotide 1468 of KCNH2, which results in a substitution of alanine by threonine (A490T) (B). DNA sequence for KCNH2 SNP K897T is shown in (C). (D) Comparison of mean QTc for carriers with KCNH2 mutation A490T, A490P, and both A490T and SNP K897T.

Mentions: Family QW2648 is a LQTS family with 11 family members (Fig. 1A). Two family members, I:1and II:2, had QTc of 0.47 s or higher (Fig. 1A). Linkage analysis for family QW2648 showed linkage to D7S798 near the LQT2 locus (Fig. 1A). Direct DNA sequence analysis of the DNA from the proband in the family identified two variants in KCNH2: a heterozygous G→A transition at nucleotide 1468, which results in a substitution of amino acid residue alanine by threonine (A490T) (Fig. 1B) and a heterozygous A→C transition at nucleotide 2690, which results in a substitution of amino acid residue lysine by threonine (K897T) (Fig. 1C). In the family, A490T co-segregated with K897T, suggesting that the K897T and A490T variants are in the cis orientation on the same chromosome (Fig. 1A). The normal family members did not carry either of the two variants.


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 and co-segregation of KCNH2 mutation A490T and SNP K897T in family QW2648 and with LQTS. (A). Pedigree structure of family QW2648. All the affected individuals carry double variants, K897T and A490T of KCNH2 on the same chromosome (in cis orientation). (B, C). DNA sequence analysis for the proband in family QW2648. A heterozygous G→A transition at nucleotide 1468 of KCNH2, which results in a substitution of alanine by threonine (A490T) (B). DNA sequence for KCNH2 SNP K897T is shown in (C). (D) Comparison of mean QTc for carriers with KCNH2 mutation A490T, A490P, and both A490T and SNP K897T.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Identification and co-segregation of KCNH2 mutation A490T and SNP K897T in family QW2648 and with LQTS. (A). Pedigree structure of family QW2648. All the affected individuals carry double variants, K897T and A490T of KCNH2 on the same chromosome (in cis orientation). (B, C). DNA sequence analysis for the proband in family QW2648. A heterozygous G→A transition at nucleotide 1468 of KCNH2, which results in a substitution of alanine by threonine (A490T) (B). DNA sequence for KCNH2 SNP K897T is shown in (C). (D) Comparison of mean QTc for carriers with KCNH2 mutation A490T, A490P, and both A490T and SNP K897T.
Mentions: Family QW2648 is a LQTS family with 11 family members (Fig. 1A). Two family members, I:1and II:2, had QTc of 0.47 s or higher (Fig. 1A). Linkage analysis for family QW2648 showed linkage to D7S798 near the LQT2 locus (Fig. 1A). Direct DNA sequence analysis of the DNA from the proband in the family identified two variants in KCNH2: a heterozygous G→A transition at nucleotide 1468, which results in a substitution of amino acid residue alanine by threonine (A490T) (Fig. 1B) and a heterozygous A→C transition at nucleotide 2690, which results in a substitution of amino acid residue lysine by threonine (K897T) (Fig. 1C). In the family, A490T co-segregated with K897T, suggesting that the K897T and A490T variants are in the cis orientation on the same chromosome (Fig. 1A). The normal family members did not carry either of the two variants.

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