Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-05-11
2003-12-16
Myers, Carla J. (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023500, C536S024310, C536S024330
Reexamination Certificate
active
06664055
ABSTRACT:
FIELD OF INVENTION
The present invention relates generally to the identification of cell receptors and encoding genes that are involved in neurological disease and the identification of receptors and encoding genes involved in mono and bipolar mood disorders.
BACKGROUND OF THE INVENTION
Mood disorders rank among the top ten causes of disability worldwide. Unipolar depressive disorder and bipolar disorder are mood disorders with high prevalence in the population and an enormous impact on the life of affected individuals and society (Oruc et al., (1998a)
Med. Arch.,
52:107-112; Craddock and Jones, (1999)
Am. J. Psychiatry,
149443-454; Oruc et al., (1998b)
Med. Arch,
52:167-173; Doris et al., (1999)
Lancet,
354:1369-1375). Disability and suffering from a mood disorder even extends beyond the patient to their spouses, children, parents, siblings, and friends, who experience frustration, guilt, anger, financial hardship and, on occasion, physical abuse, all in their attempts to assuage or cope with the depressed person's suffering. A large portion of health care expenditures go to treating individuals having depression. Paradoxically, much of treatment does not address the mood disorder because individuals try to seek treatment for other problems in order to avoid the stigma associated with having a mood disorder diagnosis. Consequently, patients with depression undergo extensive and expensive diagnostic procedures of no benefit while their mood disorder goes undiagnosed.
The genetics of mood disorders appears complex and it has been proposed that anticipation and/or genomic imprinting of candidate genes contribute to the observed mode of inheritance (Grigoroiu-Serbanescu (1992)
Rom J Neural Psychiatry,
30,265-277. Grigoroiu-Serbanescu (1995)
Acta Psychiatr Scand,
92, 365-370. ; McMahon, et al. (1995)
Am J Hum Genet,
56, 1277-1286; Kato, et al. (1996)
Am J Med Genet,
67, 546-550; Grigoroiu-Serbanescu, et al.(1997)
Br J Psychiatry,
170, 162-166). Researchers have identified genes generally involved in neurodegenerative disease such as genes of serotonergic, catecholaminergic or GABAergic neurotransmitter systems as well as the genes of the glutamate receptor system. Despite these intensive research efforts, the specific genes involved in mood disorder pathology remain to be identified.
Thus, it would be useful to identify the genes involved in mood disorders so as to improve diagnosis and therapy. The present invention addresses these needs and provide related advantages as well.
SUMMARY OF THE INVENTION
In accordance with the present invention, there are provided methods of determining predisposition of a subject to a mood disorder by determining the presence of a kainate receptor subunit GluR7 allelic genotype or allelic phenotype. In one embodiment, the allelic genotype is homozygosity for a thymine containing nucleotide at position 928 (928T/T) or homozygosity for a guanine containing nucleotide position 928 (928G/G). The T/T homozygosity is associated with recurrent unipolar depressive disorder while the G/G homozygosity is associated with bipolar II depressive disorder. Various approaches for detecting the GluR7 allelic genotype are also described. A GluR7 allelic phenotype resulting from the nucleotide polymorphism at position 928 results in homozygosity for a serine amino acid at amino acid position 310 (310 Ser/Ser) or homozygosity for an alanine at amino acid position 310 (310 Ala/Ala). The present invention also includes detection of other nucleotide bases in the codon that encode either the alanine or serine at position 928.
Also provided is a method of determining predisposition of a subject to a mood disorder for a subject having a T/G heterozygosity at nucleotide position 928 in the GluR7 gene, the method comprising determining in a biological sample of the subject, a predominance in the expression of either the T allele or the G allele. In a specific embodiment, the predominance of one allele over the other is 1.2 fold or greater. Methods for measuring GluR7 allele expression at the mRNA or protein level are also provided.
The present invention also includes a method of treating or preventing a mood disorder effected by abnormal GluR7 receptor subunit activity or function in a subject. The method comprises administering to a subject an effective amount of a compound that modulates GluR7 receptor subunit activity or function.
Also included is a method for identifying such a compound by incubating a cell expressing a GluR7 receptor subunit with a test compound under conditions sufficient to permit the test compound to interact with the cell and comparing the activity or function of said GluR7 receptor subunit when incubated in the presence of the compound with the activity or function of a GluR7 receptor subunit when incubated in the absence of the compound.
Further included are kits for carrying out the methods of the invention.
Still further included are transgenic non-human animals that express a human GluR7 allele.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, it has been discovered that particular nucleotide polymorphisms in the kainate receptor subunit GluR7 are associated with a mood disorder. Nucleotide polymorphism at nucleotide base position 928 in the cDNA of the GRIK3 gene (GenBank Accession Number U16127) results in either a T or a G. As disclosed herein, an individual who is homozygous T/T at 928 of GluR7 has a predisposition to recurrent unipolar depressive disorder. In contrast, an individual who is homozygous G/G at 928 of GluR7 has a predisposition to bipolar II depressive disorder. The present invention also includes detection of other nucleotide bases in the codon at position 928 for alanine (GCT, GCC, GCA and GCG) or serine (TCT, TCC, TCA and TCG, AGT or AGC). Furthermore, individuals heterozygous at nucleotide position 928 (T/G) have a predisposition to recurrent unipolar depressive disorder or predisposition to bipolar II depressive disorder if their expression of the T allele predominates over the G allele or vice versa, respectively. Thus, the present invention provides a method of determining predisposition of a subject to a mood disorder. In its broadest form, the method comprises determining the presence of a kainate receptor subunit GluR7 allelic genotype or allelic phenotype in a biological sample of an individual.
As used herein, “predisposition” refers to a condition of susceptibility to a disorder or disease. An individual with a predisposition to a disorder is more likely than an individual without the predisposition to develop the disorder. Accordingly, an individual predisposed to a mood disorder is more likely to develop a mood disorder than an individual without such a predisposition.
As used herein, “mood disorder” refers to a psychiatric disorder involving disturbances in thinking, emotion, or behavior. Mood disorders are psychiatric illnesses in which emotional disturbances, also called affective disorders, include prolonged periods of excessive depression or elation (mania). Chronic and recurring depressions are termed unipolar depressive disorders. Bipolar disorder, in which periods of depression alternate with periods of mania (or with periods of less severe mania known as hypomania) affects nearly 2 percent of the population. Manic-depressive illness usually begins with depression and includes at least one period of mania at some time during the illness. Episodes of depression typically last 3 to 6 months. In the most severe form of the illness, called bipolar I disorder, depression alternates with intense mania. In the less severe form, called bipolar II disorder, short depressive episodes alternate with hypomania. Symptoms of bipolar II disorder often recur in certain seasons, for example, depression occurs in the fall and winter, and brief excitement occurs in the spring or summer. In an even milder form of manic-depressive illness, called cyclothymic disorder, periods of elation and depression are less severe, typically last for only a few days, and recur fairly o
Heinemann Stephen F.
Schiffer Hans H.
Foley & Lardner
Myers Carla J.
Sakelaris Sally
The Salk Institute
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