Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-12-07
2001-07-17
Myers, Carla J. (Department: 1655)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024310, C435S006120, C435S091200, C435S810000
Reexamination Certificate
active
06262250
ABSTRACT:
STATEMENT AS TO RIGHTS TO INVENTION
The present invention was developed at Massachusetts General Hospital under obligation to assign the invention to the same. The Dysautonomia Foundation has an option for an exclusive license for the present invention.
FIELD OF THE INVENTION
This invention relates to genetic testing; more specifically, to a method of detecting the presence of the familial dysautonomia gene and also the identification of the location of the familial dysautonomia gene in the genome.
BACKGROUND OF THE INVENTION
Familial dysautonomia, or the Riley-Day syndrome, is a rare inherited neurological disease affecting the development and survival of sensory, sympathetic and some parasympathetic neurons (Riley, C. M. et al.,
Pediatrics
1949; 3:468-477; Axelrod, F. B., et al.,
Am. J. Dis. Child
. 1984; 138:947-954; Axelrod, F. B.,
Cell. Molec. Biol. Neuronal Dev
. 1984; Ed.: Black, I. B., Plenum Press, N.Y.; 331-340). It is the most common and the best known of a group of rare disorders, termed congenital sensory neuropathies, that are characterized by widespread sensory, and variable autonomic dysfunction. Patients with familial dysautonomia are affected from birth with a variety of symptoms such as decreased sensitivity to pain and temperature, vomiting crises and cardiovascular instability all of which might result from a deficiency in a neuronal growth factor pathway (Breakefield, X. O., et al.,
Proc. Natl. Acad. Sci. USA
1984; 81:4213-4216; Breakefield, X. O., et al.,
Mol. Biol. Med
. 1986; 3:483-494). Neuropathological findings have clearly differentiated familial dysautonomia from other congenital sensory neuropathies (Axelrod, F. B., et al.,
Am. J. Dis. Child
., supra, Axelrod, F. B.,
Cell. Molec. Biol. Neuronal Dev
., supra.) The disorder is inherited as an autosomal recessive with complete penetrance and is currently confined to individuals of Ashkenazi Jewish descent (Brunt, P. W., et al.,
Medicine
1970; 49:343-374). In this population, the estimated carrier frequency is 1 in 30 with a disease incidence of 1 in 3600 births (Maayan, C., et al.,
Clinical Genet
. 1987; 32:106-108). The clear-cut pattern of transmission, apparent restriction to one ethnic population and lack of confounding phenocopies suggest that all cases of familial dysautonomia might have descended from a single mutation (Axelrod, F. B., et al.,
Am. J. Dis. Child
., supra, Axelrod, F. B., Cell.
Molec. Biol. Neuronal Dev
., supra).
For more than 40 years, familial dysautonomia related research concentrated on biochemical, physiological and histological-pathological aspects of the disorder. Although those studies contributed to a better understanding of the nature of the disease, and indicated that a deficiency in a neuronal growth factor pathway might be the cause of familial dysautonomia, they did not result in identification of the familial dysautonomia gene, thus, those studies did not contribute to the availability of a genetic test for familial dysautonomia.
Chromosomal localization of the gene causing familial dysautonomia can facilitate genetic counseling and prenatal diagnosis in affected families. Subsequent delineation of closely linked markers which show strong linkage disequilibrium with the disorder and ultimately, identification of the defective gene can allow screening of the entire at-risk population to identify carriers, and potentially reduce the incidence of new cases.
Linkage analysis can be used to find the location of a gene causing a hereditary disorder and does not require any knowledge of the biochemical nature of the disease, i.e. the mutated protein that is believed to cause the disease. Traditional approaches depend on assumptions concerning the disease process that might implicate a known protein as a candidate to be evaluated. The genetic localization approach using linkage analysis (positional cloning) can be used to first find the chromosomal region in which the defective gene is located and then to gradually reduce the size of the region in order to determine the location of the specific mutated gene as precisely as possible. After the gene itself is identified within the candidate region, the messenger RNA and the protein are identified and along with the DNA, are checked for mutations.
This latter approach has practical implications since the location of the gene can be used for prenatal diagnosis even before the altered gene that causes the disease is found. Identification of DNA markers linked to the disease gene will enable molecular diagnosis of carriers of the disease gene for familial dysautonomia and the determination of the probability of having the disease. This identification of the presence of the disease gene also enables persons to evaluate either genetic probability of passing this gene to their offspring or the presence of the mutated gene in an unborn child. The mutation(s) in the specific gene responsible for the pathogenesis of familial dysautonomia has its origin in the Ashkenazi Jewish population. Accordingly, individuals of Ashkenazi Jewish descent are at greatest risk of carrying the altered gene.
The transmission of a disease within families, then, can be used to find the defective gene. This approach to molecular etiology is especially useful in studies of inherited neurologic disorders, as only several thousands of the hundred-or-so thousand genes active in the nervous system are known, and nervous tissue is hard to obtain for biochemical analysis.
Linkage analysis is possible because of the nature of inheritance of chromosomes from parents to offspring. During meiosis the two homologues pair to guide their proper separation to daughter cells. While they are lined up and paired, the two homologues exchange pieces of the chromosomes, in an event called “crossing over” or “recombination”. The resulting chromosomes are chimeric, that is, they contain parts that originate from both parental homologues. The closer together two sequences are on the chromosome, the less likely that a recombination event will occur between them, and the more closely linked they are. In a linkage analysis experiment, two positions on a chromosome are followed from one generation to the next to determine the frequency of recombination between them. In a study of an inherited disease, one of the chromosomal positions is marked by the disease gene or its normal counterpart, i.e. the inheritance of the chromosomal region can be determined by examining whether the individual displays symptoms of the disorder or is a parent of an affected individual (carrier) or not. The other position is marked by a DNA sequence that shows natural variation in the population such that the two homologues can be distinguished based on the copy of the “marker” sequence that they possess. In every family, the inheritance of the genetic marker sequence is compared to the inheritance of the disease state. If within a family carrying a recessive disorder such as familial dysautonomia every affected individual carries the same form of the marker and all the unaffected individuals carry at least one different form of the marker, there is a great probability that the disease gene and the marker are located close to each other. In this way, chromosomes may be systematically checked with known markers and compared to the disease state. The data obtained from the different families is combined, and analyzed together by a computer using statistical methods. The result is information indicating the probability of linkage between the genetic marker and the disease gene at different distance intervals. A positive result indicates that the disease is very close to the marker, while a negative result indicates that it is far away on that chromosome, or on an entirely different chromosome.
Linkage analysis is performed by typing all members of the affected family at a given marker locus and evaluating the co-inheritance of a particular disease gene with the marker probe, thereby determining whether the two of them are close to each other in the genome. The recombination frequency can be u
Blumenfeld Anat
Breakefield Xandra O.
Gusella James F.
Slaugenhaupt Susan
Morgan & Finnegan L.L.P.
Myers Carla J.
The General Hospital Corporation
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