Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1996-06-17
2000-05-30
Brusca, John S.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 691, 435 914, 4353201, 435325, 536 235, C12Q 168, C12P 2100, C12N 500, C07H 2104
Patent
active
060689757
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Throughout this application, various references are referred to within parenthesis. Disclosures of these publication in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of each series of experiments in the Experimental Details section.
Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism with a world-wide prevalence of 30 per million and a corresponding carrier frequency of 1 in 90. Biochemically it is characterized by abnormally high concentrations of copper in a number of organs and tissues, and deficiency of the plasma copper-protein, ceruloplasmin. The excess copper causes damage to the liver and brain. In the former, acute and chronic hepatic disease progresses to cirrhosis; in the latter motor and psychiatric disturbances reflect the cerebral pathology. Clinical onset may occur in the latter half of the first decade, is most frequent in adolescence, and was delayed in two patients until the seventh decade. Untreated, the disease is always fatal but pharmacologic removal or detoxification of the excess copper is prophylactic in the asymptomatic patient and can be dramatically effective therapy for patients with hepatic or cerebral symptomatology. The mechanism by which the abnormal gene disturbs copper homeostasis is unknown (1).
In 1985, genetic linkage studies showed that the Wilson's disease locus segregates with the red cell enzyme esterase-D (ESD) on chromosome 13 (2). Subsequent linkage analyses limited the disease locus to a genomic region bracketed by the DNA marker loci D13S31 and D13S59, although the odds for a disease locus in the adjacent interval between loci D13S31 and D13S25 were estimated to be only seven times less likely (3).
SUMMARY OF THE INVENTION
This invention provides an isolated, vertebrate nucleic acid molecule encoding the normal polypeptide which prevents development of Wilson's disease. This invention also provides the above-described isolated, vertebrate nucleic acid molecule operatively linked to a promoter of RNA transcription.
This invention also provides a nucleic acid molecule comprising a nucleic acid molecule of at least 15 nucleotides capable of specifically hybridizing with a sequence included within the sequence of the nucleic acid molecule encoding the normal polypeptide which prevents development of Wilson's disease.
This invention provides a host vector system for the production of a polypeptide which prevents the development of Wilson's disease.
This invention further provides the normal polypeptide which prevents development of Wilson's disease.
This invention also provides an antibody capable of binding to polypeptide encoded by an isolated, vertebrate nucleic acid molecule encoding the normal polypeptide which prevents development of Wilson's disease.
This invention further provides a method for diagnosing Wilson's disease in a subject comprising: (a) obtaining nucleic acid sample from the subject; (b) reverse-transcribing the RNA to cDNA if the obtained nucleic acid from step (a) is RNA; (c) cleave the DNA sample into fragments; (d) separating the DNA fragments by size fractionation; (e) hybridizing the DNA fragments with a nucleic acid molecule comprising a nucleic acid molecule of at least 15 nucleotides capable of specifically hybridizing with a sequence included within the sequence of the nucleic acid molecule encoding the normal polypeptide which prevents development of Wilson's disease; and (f) comparing the detected DNA fragment from (d) with the DNA fragment from a known normal subject, the difference in size of the fragments indicating the occurrence of Wilson's disease in the subject.
This invention provides a method for diagnosing Wilson's disease in a subject comprising: (a) obtaining RNA sample from the subject; (b) separating the RNA sample into different species by size fractionation; (c) hybridizin g the RNA
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Gilliam T. Conrad
Tanzi Rudolph E.
Brusca John S.
General Hospital Corporation
Sandals William
The Trustees of Columbia University in the City of New York
White John P.
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