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(Circulation. 1997;95:565-567.)
© 1997 American Heart Association, Inc.

Articles

Four Novel KVLQT1 and Four Novel HERG Mutations in Familial Long-QT Syndrome

Toshihiro Tanaka, MD; Ryozo Nagai, MD; Hitonobu Tomoike, MD; Shigeo Takata, MD; Katsusuke Yano, MD; Keijiro Yabuta, MD; Noriyuki Haneda, MD; Osami Nakano, MD; Akira Shibata, MD; Toshitami Sawayama, MD; Hideaki Kasai, MD; Yoshio Yazaki, MD; Yusuke Nakamura, MD, PhD

the Laboratory of Molecular Medicine, Institute of Medical Science, University of Tokyo (T.T., Y.N.); Second Department of Internal Medicine, Gunma University School of Medicine (R.N.); First Department of Internal Medicine, Yamagata University School of Medicine (H.T.); First Department of Internal Medicine, School of Medicine, Kanazawa University (S.T.); Third Department of Internal Medicine, School of Medicine, Nagasaki University (K. Yano); Department of Pediatrics, School of Medicine, Juntendo University, Tokyo (K. Yabuta); Department of Pediatrics, Shimane Medical University (N.H.); Department of Pediatrics, Takamatsu Municipal Hospital, Kagawa (O.N.); First Department of Internal Medicine, School of Medicine, Niigata University (A.S.); Division of Cardiology, Department of Medicine, Kawasaki Medical School, Okayama (T.S.); Department of Cardiology, Metropolitan Kiyose Children's Hospital, Tokyo (H.K.); and Department of Internal Medicine III, University of Tokyo School of Medicine (Y.Y.), Japan.

Correspondence to Toshihiro Tanaka, MD, Laboratory of Molecular Medicine, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108, Japan. E-mail toshitan@ims.u-tokyo.ac.jp.

	Abstract

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Background Familial long-QT syndrome (LQTS) is characterized by prolonged ventricular repolarization. Clinical symptoms include recurrent syncopal attacks, and sudden death may occur due to ventricular tachyarrhythmias. Three genes responsible for this syndrome (KVLQT1, HERG, and SCN5A) have been identified so far. We investigated mutations of these genes in LQTS families.

Methods and Results Thirty-two Japanese families with LQTS were brought together for screening for mutations. Genomic DNA from each proband was examined by the polymerase chain reaction–single-strand conformation polymorphism technique followed by direct DNA sequencing. In four of the families, comprising 16 patients, mutations were identified in KVLQT1; five other families (9 patients) segregated mutant alleles of HERG. All 25 of these patients carried the specific mutations present in their respective families, and none of 80 normal individuals carried these alleles. Mutations were confirmed by endonuclease digestion or hybridization of mutant allele–specific oligonucleotides. No mutation in SCN5A was found in any family.

Conclusions We identified nine different mutations among 32 families with LQTS. Eight of these were novel and account for 25% of all types of mutations reported to date. Such a variety of mutations makes it difficult to screen high-risk groups using simple methods such as endonuclease digestion or mutant allele–specific amplification.

Key Words: genes • intervals • genetics • death, sudden • torsade de pointes • tachyarrhythmia

	Introduction

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Familial long-QT syndrome (LQTS) is characterized by prolongation of the QT_c interval on ECG. Some patients suffer from recurrent syncopal attacks and are at high risk of sudden death. Because the first symptom can sometimes be lethal, presymptomatic diagnosis is of significant importance so that preventive measures can be taken, eg, administration of an antiarrhythmic drug or implantation of an automatic defibrillator. However, definitive diagnosis is difficult because the QT_c intervals and clinical signs vary among individuals.¹ Genetic diagnosis using polymorphic DNA markers could be useful, but finding appropriate polymorphic DNA markers is troublesome, especially for small families, because of genetic heterogeneity.^{2 3 4} Furthermore, because LQTS may be a factor underlying incidents of sudden death among school children and young adults subsequent to physical stress, it is clinically and socially important to develop some means for screening high-risk groups.

For patients with clinical symptoms, ß-adrenergic blocking agents are the first choice for treatment. Approximately 80% of LQTS patients can be managed effectively with these drugs, but the remaining 20% do not respond.⁵ Hence, if the different responses reflect mutations at different sites within a given gene or mutations in different genes, genetic diagnosis might provide information to govern the choice of an appropriate therapeutic approach.

Recently, three genes responsible for LQTS were identified. Two encode potassium-channel subunits (KVLQT1⁶ and HERG⁷ ) and the other encodes a sodium-channel subunit (SCN5A⁸ ). So far, 12 mutations in KVLQT1,^{6 9} 9 in HERG,^{7 10 11} and 3 in SCN5A^{8 12} have been identified. Although there seems to be one mutational hot spot (nucleotide 212 in KVLQT1; 8 of 34 LQTS families), it would not enable us to screen many people by means of endonuclease digestion or mutant allele–specific amplification methods.¹³

In the present study, we report mutations in KVLQT1 and HERG among 9 of 32 Japanese families examined.

	Methods

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Diagnosis of Patients
DNA samples from 32 families with LQTS and those from 80 normal individuals, along with individual and family histories and ECG records, were collected throughout Japan. To avoid bias, QT_c intervals were measured by physicians who were not involved in the mutation analyses. Peripheral blood samples were obtained with informed consent of the patients and members of their families. Phenotypic determinations were made on the basis of the QT_c interval,¹⁴ as described previously.^{15 16}

Mutational Analysis
DNA from the proband of each family was analyzed by polymerase chain reaction–single-strand conformation polymorphism (PCR-SSCP). Primers for genomic amplification and sequencing were described previously.^{6 7 8} Cycling conditions were 35 cycles of 94°C for 30 seconds, 58°C for 30 seconds, and 72°C for 60 seconds. Each reaction mixture was diluted with 95% formamide dye, incubated at 80°C for 5 minutes, and applied to a 6% polyacrylamide gel containing 0.5x Tris-borate-EDTA buffer and 5% glycerol. Electrophoresis was performed at 4°C. Gels were dried and autoradiographed with intensifying screens.

For DNA sequencing, genomic DNA (20 ng) from each patient showing an aberrant conformer in PCR-SSCP analysis was amplified in a 25-mL PCR reaction as above. After removal of dNTPs and primers by columns, each sample was subjected to cycle sequencing using a dye terminator cycle-sequencing kit (Perkin-Elmer) according to the supplier's instructions. Electrophoresis was performed with the use of a 377 DNA sequencer (Perkin-Elmer). When a new recognition site of an endonuclease was made by a mutation, PCR products of DNAs from all available family members and from 80 normal individuals were digested by that enzyme and applied to a nondenaturing polyacrylamide gel for confirmation of the mutation. For additional confirmation, we also performed hybridization of mutant allele-specific oligonucleotides.¹⁷

	Results

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In all, nine different mutations were scattered in the coding region in either KVLQT1 or HERG (Table). Because all of them were missense mutations, we cannot completely exclude the possibility of very rare polymorphisms. However, because each of these mutations cosegregated among patients showing a prolonged QT_c interval on ECGs and none of the nucleotide changes were seen among 80 normal individuals, these mutations are likely to have caused the disease. Among the nine families in which mutations were found, four (16 patients) segregated a mutated KVLQT1 allele and five (9 patients) a mutated HERG allele. No mutation was found in SCN5A in our panel of 32 families. The Figure illustrates the mutation and cosegregation of KVLQT1 within a representative family.

View this table: [in this window] [in a new window]   Table 1. Summary of LQT Mutations

View larger version (33K): [in this window] [in a new window]   Figure 1. KVLQT1 mutation and its segregation in family (fam) 56. Left, By fluorescent sequencing, patient 5604 (indicated by an asterisk in the pedigree on the right) was shown to carry a C552G mutation, which causes an amino acid change from isoleucine to methionine in the pore region of the KVLQT1 gene (see also the Table). Sequences of the antisense strand are shown. Bottom right, Endonuclease NlaIII, which cleaves DNA at CATG sequences, was used for confirmation. Because the mutant allele has a CATG sequence where the normal allele is GATG, the two alleles can be distinguished by NlaIII digestion and size fractionation with the use of acrylamide gel electrophoresis. In this case, the size of the normal polymerase chain reaction product is 196 bp; NlaIII digestion of the mutant allele divided it into 148-bp and 48-bp fragments. Each lane corresponds to the member of family 56 indicated above in the pedigree. In the pedigree shown at the top right of the Figure, black indicates affected; white, unaffected; and shaded, unknown phenotype.

	Discussion

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In this study, we identified four different mutations in KVLQT1 and five in HERG. Eight of them had not been reported before. Including previous reports,^{6 7 8 9 10 11 12} 32 types of mutations have been identified so far in 43 families. Although mutations at nucleotide 212 in KVLQT1 have been observed in 8 families (18.6%) and therefore this location seems to be a mutational hot spot, we did not identify such mutations in Japanese families, and the possibility of the founder effect could not be excluded. These data also indicate that detecting high-risk groups by screening for mutations is a difficult strategy.

Only 12.5% of our panel of 32 Japanese families with LQTS were shown to have mutations in KVLQT1, an unexpected finding in view of the linkage studies indicating that more than half of all LQTS patients may have mutations in KVLQT1.⁶ Possible reasons for the discrepancy include the following: (1) some families are too small to define the responsible genetic loci by linkage analysis; (2) because the entire coding region of KVLQT1 has not yet been cloned, mutational analysis cannot investigate the entire gene; and (3) another gene(s) responsible for LQTS may be located close to KVLQT1.

The relationship between KVLQT1 mutations and clinical symptoms is not yet clear. Patients with mutated SCN5A may be more likely to benefit from Na⁺ channel blockers,¹⁸ and an increase in serum potassium is shown to correct abnormalities of repolarization duration, T-wave morphology, QT/RR slope, and QT dispersion.¹⁹ Our preliminary, unpublished data may indicate that among symptomatic patients, those who have a mutated KVLQT1 allele show a better response to ß-blocking agents; this requires additional validation.

It also remains a mystery why a single family may contain clinically symptomatic and asymptomatic carriers of a mutant LQTS allele, all of them exhibiting prolongation of the QT_c interval. It is likely that factors other than genetic ones, such as a hormonal environment that may cause an imbalance between activities of the sympathetic and parasympathetic nerves, may generate variations in the clinical phenotype. This issue is highly important for understanding the mechanism of ventricular arrhythmias.

	Acknowledgments

 
This work was supported in part by a grant-in-aid from the Science and Technology Agency and the Ministry of Education, Science, Sports, and Culture, Japan.

Received October 31, 1996; revision received December 6, 1996; accepted December 9, 1996.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tanaka, T. Articles by Nakamura, Y. Search for Related Content PubMed PubMed Citation Articles by Tanaka, T. Articles by Nakamura, Y.