Alterations in the long QT syndrome genes KVLQT1 and SCN5A...

Details Alterations in the long QT syndrome genes KVLQT1 and SCN5A... Alterations in the long QT syndrome genes KVLQT1 and SCN5A...

2001-04-24

2004-09-07

Sitton, Jehanne (Department: 1634)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S071100, C435S091100, C435S091200, C536S023100, C536S024300

Reexamination Certificate

active

06787309

ABSTRACT:

BACKGROUND OF THE INVENTION
Long QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on electrocardiogram and presence of syncope, seizures and sudden death, usually in young, otherwise healthy individuals (Jervell and Lange-Nielsen, 1957; Romano et al., 1963; Ward, 1964). The clinical features of LQTS result from episodic ventricular tachyarrhythmias, such as torsade de pointes and ventricular fibrillation (Schwartz et al., 1975; Moss et al., 1991). Two inherited forms of LQTS exist. The more common form, Romano-Ward syndrome (RW), is not associated with other phenotypic abnormalities and is inherited as an autosomal dominant trait with variable penetrance (Roman et al., 1963; Ward, 1964). Jervell and Lange-Nielsen syndrome (JLN) is characterized by the presence of deafness, a phenotypic abnormality inherited as an autosomal recessive trait (Jervell and Lange-Nielsen, 1957). LQTS can also be acquired, usually as a result of pharmacologic therapy.
In previous studies, we mapped LQTS loci to chromosomes 11p15.5 (LQT1) (Keating et al., 1991), 7 q35-36 (LQT2) (Jiang et al., 1994) and LQT3 to 3p21-24 (Jiang et al., 1994). A fourth locus (LQT4) was mapped to 4q25-27 (Schott et al., 1995). Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS. These genes are KVLQT1 (LQT1) (Wang Q. et al., 1996a), HERG (LQT2) (Curran et al., 1995), SCN5A (LQT3) (Wang et al., 1995a), and two genes located at 21q22-KCNE1 (LQT5) (Splawski et al., 1997a) and KCNE2 (LQT6) (Abbott et al., 1999). Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion.
KVLQT1, HERG, KCNE1 and KCNE2 encode potassium channel subunits. Four KVLQT1 &agr;-subunits assemble with minK (&bgr;-subunits encoded by KCNE1, stoichiometry is unknown) to form I
Ks
channels underlying the slowly activating delayed rectifier potassium current in the heart (Sanguinetti et al., 1996a; Barhanin et al., 1996). Four HERG &agr;-subunits assemble with MiRP1 (encoded by KCNE2, stoichiometry unknown) to form I
Kr
channels, which underlie the rapidly activating, delayed rectifier potassium current (Abbott et al., 1999). Mutant subunits lead to reduction of I
Ks
or I
Kr
by a loss-of-function mechanism, often with a dominant-negative effect (Chouabe et al., 1997; Shalaby et al., 1997; Wollnik et al., 1997; Sanguinetti et al., 1996b). SCN5A encodes the cardiac sodium channel that is responsible for I
Na
, the sodium current in the heart (Gellens et al., 1992). LQTS-associated mutations in SCN5A cause a gain-of-function (Bennett et al., 1995; Dumaine et al., 1996). In the heart, reduced I
Ks
or I
Kr
or increased I
Na
leads to prolongation of the cardiac action potential, lengthening of the QT interval and increased risk of arrhythmia. KVLQT1 and KCNE1 are also expressed in the inner ear (Neyroud et al., 1997; Vetter et al., 1996). Others and we demonstrated that complete loss of I
Ks
causes the severe cardiac phenotype and deafness in JLN (Neyroud et al., 1997; Splawski et al., 1997b; Tyson et al., 1997; Schulze-Bahr et al., 1997).
Presymptomatic diagnosis of LQTS is currently based on prolongation of the QT interval on electrocardiogram. Genetic studies, however, have shown that diagnosis based solely on electrocardiogram is neither sensitive nor specific (Vincent et al., 1992; Priori et al., 1999). Genetic screening using mutational analysis can improve presymptomatic diagnosis. However, a comprehensive study identifying and cataloging all LQTS-associated mutations in all five genes has not been achieved. To determine the relative frequency of mutations in each gene, facilitate presymptomatic diagnosis and enable genotype-phenotype studies, we screened a pool of 262 unrelated individuals with LQTS for mutations in the five defined genes. The results of these studies are presented in the Examples below.
The present invention relates to alterations in the KVLQT1, HERG, SCN5A, KCNE1 and KCNE2 genes and methods for detecting such alterations.
The publications and other materials used herein to illuminate the background of the invention or provide additional details respecting the practice, are incorporated by reference, and for convenience are respectively grouped in the appended List of References.
The present invention is directed to alterations in genes and gene products associated with long QT syndrome and to a process for the diagnosis and prevention of LQTS. LQTS diagnosed in accordance with the present invention by analyzing the DNA sequence of the KVLQT1, HERG, SCN5A, KCNE1 or KCNE2 gene of an individual to be tested and comparing the respective DNA sequence to the known DNA sequence of the normal gene. Alternatively, these genes of an individual to be tested can be screened for mutations which cause LQTS. Prediction of LQTS will enable practitioners to prevent this disorder using existing medical therapy.
SUMMARY OF THE INVENTION
The present invention relates to alterations in the KVLQT1, HERG, SCN5A, KCNE1 and KCNE2 genes and methods for detecting such alterations. The alterations in the KVLQT1, HERG, SCN5A, KCNE1 and KCNE2 genes include mutations and polymorphisms. Included among the mutations are frameshift, nonsense, splice, regulatory and missense mutations. Any method which is capable of detecting the alterations described herein can be used. Such methods include, but are not limited to, DNA sequencing, allele-specific probing, mismatch detection, single stranded conformation polymorphism detection and allele-specific PCR amplification.


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