QUARTERLY FOCUS ISSUE: HEART RHYTHM DISORDERS: CLINICAL RESEARCH
D85N, a KCNE1 Polymorphism, Is a Disease-Causing Gene Variant in Long QT Syndrome
Yukiko Nishio, MD*,
Takeru Makiyama, MD, PhD*,
Hideki Itoh, MD, PhD ,
Tomoko Sakaguchi, MD, PhD,
Seiko Ohno, MD, PhD*,
Yin-Zhi Gong, MD, PhD,
Satoshi Yamamoto, MD ,
Tomoya Ozawa, MD, PhD,
Wei-Guang Ding, MD, PhD ,
Futoshi Toyoda, PhD,
Mihoko Kawamura, MD,
Masaharu Akao, MD, PhD*,
Hiroshi Matsuura, MD, PhD,
Takeshi Kimura, MD, PhD*,
Toru Kita, MD, PhD* and
Minoru Horie, MD, PhD,*
* Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Shiga, Japan
Department of Physiology, Shiga University of Medical Science, Shiga, Japan
Third Department of Internal Medicine, Osaka Medical College, Osaka, Japan
Manuscript received September 8, 2008;
revised manuscript received May 21, 2009,
accepted June 15, 2009.
* Reprint requests and correspondence: Dr. Minoru Horie, Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan (Email: horie{at}belle.shiga-med.ac.jp).
Objectives: This study aims to address whether D85N, a KCNE1 polymorphism, is a gene variant that causes long QT syndrome (LQTS) phenotype.
Background: KCNE1 encodes the beta-subunit of cardiac voltage-gated K+ channels and causes LQTS, which is characterized by the prolongation of the QT interval and torsades de pointes, a lethal arrhythmia. D85N, a KCNE1 polymorphism, is known to be a functional variant associated with drug-induced LQTS.
Methods: In order to elucidate the prevalence and clinical significance of this polymorphism, we performed genetic screening in 317 LQTS probands. For comparison, we examined its presence in 496 healthy control subjects. We also conducted biophysical assays for the D85N variant in mammalian cells.
Results: The allele frequency for D85N carriers was 0.81% in healthy people. In contrast, among LQTS probands, there were 1 homozygous and 23 heterozygous carriers (allele frequency 3.9%). Seven of 23 heterozygous carriers had additional mutations in LQTS-related genes, and 3 female subjects had documented factors predisposing to the symptom. After excluding these probands, the D85N prevalence was significantly higher compared with control subjects (allele frequency 2.1%, p < 0.05). In a heterologous expression study with Chinese hamster ovarian cells, KCNE1-D85N was found to exert significant loss-of-function effects on both KCNQ1- and KCNH2-encoded channel currents.
Conclusions: The KCNE1-D85N polymorphism was significantly more frequent in our LQTS probands. The functional variant is a disease-causing gene variant of LQTS phenotype that functions by interacting with KCNH2 and KCNQ1. Since its allele frequency was  1% among control individuals, KCNE1-D85N may be a clinically important genetic variant.
Key Words: long QT syndrome • single nucleotide polymorphism • disease-causing variant
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Abbreviations and Acronyms
| | CHO = Chinese hamster ovarian | | LQTS = long QT syndrome | | QTc = corrected QT interval | | TdP = torsades de pointes |
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