University of Utah Research Foundation

Other

Yale University

Genzyme Corporation

University of Nevada

Univ. of Utah Research Foundation

Board of Regents of the Nevada System of Higher Education

Mark T. Keating

Colleen A. Morris

Mark T Keating

Igor Splawski

Michael C Sanguinetti

Mark E Curran

Timothy C Burn

Timothy D Connors

Gregory M Landes

Dean Li

Colleen A Morris

Mark F Leppert

Qing K Wang

Geoffrey W Abbott

Federico Sesti

Steve A N Goldstein

Thomas M Olson

Elastin, the main component of arterial extracellular matrix, was thought to have a purely structural role. Consistent with this view, elastin hemizygous mice maintain arterial extensibility by increasing the number of elastic lamellae during development. However, mice lacking elastin die of obstructive arterial pathology. This pathology results from subendothelial proliferation and reorganization of smooth muscle, cellular changes similar to those observed in atherosclerosis. Thus, elastin is a molecular determinant of arterial morphogenesis and likely plays a central role in vascular disease. Mice which are heterozygous and null for the elastin gene have been developed. These mice are extremely useful for screening for drugs useful for treating persons with atherosclerosis, hypertension, SVAS or other vascular diseases.

Mice which are +/&#x2212; or &#x2212;/&#x2212; for the elastin gene as models for vascular disease

The invention relates to the determination of the genomic structure of HERG which is a gene associated with long QT syndrome. The sequences of the 15 intron/exon junctions has been determined and this information is useful in devising primers for amplifying and sequencing across all of the exons of the gene. This is useful for determining the presence or absence of mutations which are known to cause long QT syndrome. Also disclosed are many new mutations in HERG which have been found to be associated with long QT syndrome.

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The genomic structure including the sequence of the intron/exon junctions is disclosed for KVLQT1 and KCNE1 which are genes associated with long QT syndrome. Additional sequence data for the two genes ARE also disclosed. Also disclosed are newly found mutations in KVLQT1 which result in long QT syndrome. The intron/exon junction sequence data allow for the design of primer pairs to amplify and sequence across all of the exons of the two genes. This can be used to screen persons for the presence of mutations which cause long QT syndrome. Assays can be performed to screen persons for the presence of mutations in either the DNA or proteins. The DNA and proteins may also be used in assays to screen for drugs which will be useful in treating or preventing the occurrence of long QT syndrome.

Mutations in the KCNE1 gene encoding human minK which cause arrhythmia susceptibility thereby establishing KCNE1 as an LQT gene

The present invention is directed to a specific mutation in SCN5A which causes drug-induced torsade de pointes or ventricular fibrillation. Persons with the mutation are predisposed to developing drug-induced torsade de pointes or ventricular fibrillation when administered certain drugs. This predisposition can be diagnosed in accordance with the present invention by analyzing the DNA sequence of the SCN5A of an individual. By screening patients for the mutation, drug-induced torsade de pointes or ventricular fibrillation can be avoided. Furthermore, drugs can be tested to determine whether they will cause torsade de pointes or ventricular fibrillation.

Common polymorphism in scn5a implicated in drug-induced cardiac arrhythmia

The present invention provides screening methods that use organisms or cells that lack function in one or both elastin genes. These methods are useful in identifying drugs for the prevention and treatment of obstructive vascular diseases, such as atherosclerosis, vascular restenosis and transplant arteriopathy. Further, the invention provides pharmaceutical compositions containing elastin-based compositions that are particularly potent regulators of proliferation, differentiation, and migration of smooth muscle cells in vitro and in vivo. These pharmaceutical compositions and related methods are useful in the prevention and treatment of disorders characterized by diminished capacity to regulate smooth muscle cell function.

Elastin-based compositions

KVLQT1&#x2014;a long QT syndrome gene

The present invention is directed to genes and gene products related to Min-K which form ion channels and to a process for diagnosis of ion channel disorders, including long QT syndrome (LQT). For example, KCNE2 forms Ipotassium channels and is associated with LQT. LQT is diagnosed in accordance with the present invention by analyzing the DNA sequence of KCNE2 of an individual to be tested and comparing the respective DNA sequence to the known DNA sequence of a normal KCNE2 gene. Alternatively, these MinK-related genes of an individual to be tested can be screened for mutations which cause ion channel disorders, including LQT. Prediction of ion channel disorders, including LQT, will enable practitioners to prevent the disorders using existing medical therapy. This invention is further directed to the discovery that the HERG and KCNE2 (also known as MiRP1) proteins coassemble to form a cardiac Ipotassium channel.

MinK-related genes, formation of potassium channels and association with cardiac arrhythmia

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. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS. These genes are KVLQT1, HERG, SCN5A, KCNE1 and KCNE2. 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. Mutational analyzes were used to screen 262 unrelated individuals with LQTS for mutations in the five defined genes. A total of 134 mutations were observed of which eighty were novel.

Alterations in the long QT syndrome genes KVLQT1 and SCN5A and methods for detecting same

Diagnostic method for KVLQT1&mdash;a long QT syndrome gene

KVLQT1&mdash;a long QT syndrome gene

Mutations in the KCNE1 gene encoding human mink which cause arrhythmia susceptibility thereby establishing KCNE1 as an LQT gene

KVLQT1&mdash;a long qt syndrome gene

Transgenic mice are genetically engineered for a deficiency in endoglin production. These mice may have a homozygous or hemizygous disruption of the endogenous endoglin gene. Homozygous mice exhibit a lack of endoglin production. The failure to produce endoglin results in arrested development of the vascular system of the mouse and no survival beyond E11.5. These mice and cells derived therefrom provide useful reagents for understanding the development and pathology of the mammalian vascular system.

Transgenic mouse with endogenous endoglin gene disruption

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. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS. These genes are KVLQT1, HERG, SCN5A, KCNE1 and KCNE2. 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. Mutational analyses were used to screen 262 unrelated individuals with LQTS for mutations in the five defined genes. A total of 134 mutations were observed of which eighty were novel.

Growing community of inventors

Salt Lake City, UT, United States of America

Mark T Keating