Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing saccharide radical
Reexamination Certificate
1999-02-19
2001-08-14
Whisendat, Ethan (Department: 1655)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing saccharide radical
C435S006120, C435S091200, C436S094000, C536S023100, C536S024300, C536S024310
Reexamination Certificate
active
06274352
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods for diagnosing and assessing a predisposition to bipolar affective disorder (BAD).
BACKGROUND TO THE INVENTION
BAD is a condition characterised by mood swings (mania and depression) that affects 1-2% of the population. Twin and adoption studies have shown that this disorder has a strong genetic component. However, it has a complex genetic basis and increased susceptibilty is likely due to the interplay of a number of distinct genes. The identification of a number of positive linkage results at differing chromosomal positions which supports this model of a complex genetic aetiology. Possible susceptibility loci have been reported on chromosomes 4p, 18p, 18q and 21q (Berrettini et al., 1994; Straub et al., 1994; Gurlinig et al., 1995: Stine et al., 1995; Blackwood et al., 1996: De bruyn et al., 1996: Coon et al. 1996; Freimer et al., 1996). However, no predisposing genes have ,et been identified. The present inventors have conducted a 15-cM genome screen of 214 microsatellite markers on 35 individuals from a large Australian pedigree with a history of BAD. Data were analysed by parametric two-point linkage methods using several diagnostic models. Lod scores >1.00 were obtained for 21 markers, with four of these >2.00 for at least one model. The remaining 52 individuals in the family were then genotyped with these four markers and lod scores remained positive for three markers. A more intensive screen was undertaken in these regions with the most positive results being obtained for chromosome 4q35. Using a dominant model of inheritance with 90% maximum age-specific penetrance and including bipolar I, II, schizoaffective/mania and unipolar individuals as affected, a maximum two-point lod score of 2.20 (&thgr;=0.15) at D4S1652 was obtained and a maximum three-point lod score of 3.19 obtained between D4S408 and D4S2924 was obtained. Non-parametric analyses further supported the presence of a predisposing locus on chromosome 4q35. A maximised score of 2.62 (p=0.01) was obtained between D4S1652 and D4S171 using the GENEHUNTER program, and a maximum score of 3.57(p=0.0002) was obtained at D4S2924 using the affected pedigree member (APM) method. Analysis of a further twenty-three pedigrees suggested the presence of this susceptibility locus in at least three additional families, indicating a predisposing susceptibiliy locus and not a pedigree-specific mutation. The results suggest the presence of a BAD susceptibility locus on chromosome 4q35.
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides a method of assessing an individual's predisposition to bipolar affective disorder (BAD), comprising a step of determining the presence of a BAD-linked marker(s) on chromosome 4.
Preferably, the method comprises determining the presence of a BAD-linked marker(s) at the chromosomal locus 4q35.
The method may involve the determination of a single BAD-linked marker but more preferably, involves the determination of the presence of at least two BAD-linked markers. Preferably, the BAD-linked marker(s) are microsatellite markers. More preferably, the BAD-linked marker(s) are selected from D4S1652, D4S408. D4S171 and D4S2924.
Preferably, the step of determining the presence of a BAD-linked maker(s) comprises PCR amplification and gel electrophoresis to determine the presence of a specific microsatellite allele for a given marker.
In a second aspect the present invention provides a method of assessing an individual's predisposition to bipolar affective disorder (BAD), comprising a step of analysing allelic variation in relation to a BAD susceptibility gene on chromosome 4 of the individual.
Preferably, the method of the second aspect comprises analysing allelic variation at the chromosomal locus 4q35.
Preferably, the step of analysing allelic variation comprises determining microsatellite alleles by PCR amplification and gel electrophoresis.
In a further aspect, the present invention provides a method of diagnosing bipolar affective disorder (BAD) in an individual, comprising a step of determining the presence of a BAD-linked marker(s) on chromosome
4
or, alternatively, analysing allelic variation in relation to a BAD susceptibility gene on chromosome 4.
The invention in the latter aspect may be coupled with similar screens for other susceptibility markers (e.g. markers at chromosomal loci 21q22 (Straub et al., 1994), 18p (Berretini et al., 1994) and 18q (Freimer et al., 1996), and as such may provide a valuable clinical test. An example of such a test is one in which a patient is screened for, say, 12 susceptibility loci. If the test is positive for > say 6, there is a high risk.
The present invention may be used to guide the cloning of the susceptibility gene and the identification of the allelic variation in the susceptibility gene that results in the allellic variant of the gene providing a higher relative risk, to carriers. Testing directly for this allelic variation will be the preferred diagnostic test. The method of the invention may allow identification of drugs that block or enhance the action of this gene is further likely to be of value in the clinical treatment of bipolar affective disorder.
Thus, in a third aspect, the present invention provides an isolated polynulcleotide molecule comprising a BAD susceptibility gene from the human chromosomal locus 4q35.
The terms “comprise”, “comprises” and “comprising” as used throughout the specification are intended to refer to the inclusion of a stated step, component or feature or group of steps, components or features with or without the inclusion of a further step, component or feature or group of steps, components or features.
REFERENCES:
patent: 9734928 (1997-09-01), None
patent: 9737043 (1997-10-01), None
patent: 9818963 (1998-05-01), None
Adams et al.,American Journal of Human Genetics, vol. 62, Apr. 1998, pp. 1084-1091.
Blackwood et al.,Nature Genetics, vol. 12, 1996, pp. 427-430.
Detara-Wadleigh et al.,American Journal of Medical Genetics, vol. 74, May 1997, pp. 254-262.
Van Deutekom et al., Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q 35. Human Mol. Genet., 5, 581-590, 1996.*
Van Deutekom et al., Search for the FSHD gene using cDNA selection in a region spanning 100 kb on chromosome 4q35. Muscle & Nerve, Supplement 2, S19-S26, 1995.*
Gershon et al., Maternal inheritance and chromosome 18 allele sharing in unilineal biopolar illness pedigrees. Am. J. Med.. Genet. 67, 202-207, 1996.*
Detera-Wadleigh et al., Affected-sib-pair analyses reveal support of prior evidence for a susceptibility locus for bipolar disorder, on 21q. Am. J. Hum. Genet. 58, 1279-1285, 1996.*
Detera-Wadleigh et al., A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. Proc. Natl. Acad. Sci. USA 96, 5604-5609, May 1999.*
Wijmenga et al., Chromosome 4q DNA rearrangements associated with faciioscapulohumeral muscular dystrophy. Nature Genetics 2, 26-30, 1992.*
Kwok et al., Nonparametric simulation-based statistical analyses for bipolar affective disorder locus on chromosome 21q22.3. Am. J. Med. Genet. 88, 99-102, Feb. 1999.
Adams Linda Jacqueline
Mitchell Philip Bowden
Schofield Peter Robert
Garvan Institute of Medical Research
Lu Frank
Rothwell Figg Ernst & Manbeck
Whisendat Ethan
LandOfFree
Methods for diagnosing and assessing a predisposition to... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods for diagnosing and assessing a predisposition to..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for diagnosing and assessing a predisposition to... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2443231