Method of determining susceptibility to schizophrenia

Details Method of determining susceptibility to schizophrenia Method of determining susceptibility to schizophrenia

1999-03-26

2002-05-28

Crouch, Deborah (Department: 1632)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S007100, C435S091200, C536S023500, C536S024310, C536S024330

Reexamination Certificate

active

06395482

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to isolated nucleic acid molecules which encode human and murine proline dehydrogenase, and methods for determining susceptibility to, or the presence of schizophrenia or a disease or disorder related thereto, such as obsessive compulsive disorder, bipolar disorder (BP), or major depressive disorder in a subject by determining levels of proline dehydrogenase (PRODH) in a bodily sample. Furthermore, the present invention comprises polymorphisms of the human proline dehydrogenase (PRODH) gene which correlate to a phenotype closely related to schizophrenia or a disease or disorder related thereto. The present invention also relates to various assays for drugs or agents that can treat schizophrenia or a disease or disorder related thereto.
BACKGROUND OF THE INVENTION
It has been posited that the amino acid proline serves as a modulator of synaptic transmission in the mammalian brain, due to the selective expression of a brain specific high affinity proline transporter in a subset of glutamatergic pathways (Fremeau et al., 1996). Proline transporter is modulated by enckephalins, the expression of which may be decreased in the brains of patients with schizophrenia and elevated proline concentration. Furthermore, recent analysis indicates that endogenous extracellular proline may regulate the basal function of some glutamate synapses by maintaining them in a partially potentiated state. Also, elevated proline concentration has also been previously associated with behavioral and neurological effects.
Evidence of an association between schizophrenia susceptibility and hemizygous deletions in chromosome 22q11 has been reported. More specifically, three hemizygous cryptic deletions at 22q11 in a sample of 300 unrelated schizophrenic patients have been reported and characterized [Karayiorgou et al.,
Proc. Natl. Acad. Sci. U.S.A.
92, 7612 (1995); Karayiorgou et al.,
Amer. J. Med. Genet.
74, 677 (1997)]. The frequency of this microdeletion in the general population is estimated to be approximately 0.02% and no deletions were found in a sample of 200 healthy controls. The identified locus (approximately 1.5 Mb in size) is located in the proximal part of a region at chromosome 22q11 and has been implicated independently in schizophrenia susceptibility through linkage studies [Karayiorgou & Gogos,
Neuron
19, 967-979 (1997)]. This locus overlaps with the critical region involved in the etiology of Velocardio-facial (VCFS)/DiGeorge (DGS) syndromes [Driscoll et al. 1993]. Furthermore, it has been shown that approximately 29% VCFS children with 22q11 deletions develop schizophrenia or schizoaffective disorder in adolescence and adulthood [Pulver et al., 1994], an estimate confirmed by a more recent independent study [Murphy and Owen,
Am. J. Med. Genet.,
74, 660 (1997)]. Deletions in chromosome 22, band q11 (22q11) have been identified among schizophrenia patients of diverse ethnic origins (Chinese, Israeli, British, Danish [L. Y. Chow et al.,
Am. J. Med. Genet.
74, 677 (1997); D. Gothelf et al.,
Am. J. Med. Genet.
72, 455 (1997); O. Mors and H. Ewald,
Am. J. Med. Genet.
74, 677 (1997); Hodginson et al,
Am. J. Med. Genet.
61, 565 (1997)]) and the 22q11 region has been implicated in early-onset schizophrenia [Yan et al., 1998]. In addition, the increased rates of comorbid obsessive compulsive disorder (OCD) or symptoms (OCS) among schizophrenic patients with the 22q11 microdeletion locus [Karayiorgou et al., 1996, 1997; Papolos et al., 1996] and similarly increased rates of anxiety, OCS and OCD in children and adults with the 22q11 microdeletion in the absence of schizophrenia [Papolos et al., 1996], potentially indicate that the 22q11 genomic region may harbor one or more genes predisposing to obsessive compulsive disorder (OCD).
Moreover, it has been observed that approximately 20% of schizophrenia patients report obsessions and compulsions, features that are found in only 1-2% of the general population [Eisen & Rasmussen 1993; Berman et al., 1995]. Hence, it is possible that schizophrenia and OCD may share some pathophysiological and genetic components. One common central processing mechanism that seems to be affected in patients with schizophrenia and OCD is sensorimotor gating. Patients with schizophrenia and OCD demonstrate poor sensorimotor gating of the startle response as measured by impaired prepulse inhibition of an acoustic response, and this may lead to sensory overload, distractibility and cognitive fragmentation.
However, there is no genetic marker available which is indicative of a subject's susceptibility to schizophrenia, or a disease related thereto, such as obsessive compulsive disorder (OCD), bipolar disorder (BP), or major depressive disorder (MDD).
Accordingly, what is needed is a genetic marker to assess a subject's susceptibility to schizophrenia or a disease or disorder related thereto. Also needed is a genetic marker to diagnose schizophrenia, and the development of potential drugs or agents that have applications in treating schizophrenia or a disease or disorder related thereto, such as OCD, bipolar disorder, or major depressive disorder.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.
SUMMARY OF THE INVENTION
There is provided, in accordance with the present invention, an isolated nucleic acid molecule which encodes human proline dehydrogenase, and the amino acid sequence of human proline dehydrogenase. Also provided is an isolated nucleic acid molecule comprising a DNA sequence which encodes murine proline dehydrogenase, and the amino acid sequence of murine proline dehydrogenase. Furthermore, there is provided, in accordance with the present invention, methods for determining a subject's susceptibility to schizophrenia or a disease or disorder related thereto, such as a schizoaffective disorder or disorders related thereto, like OCD, bipolar disorder, or major depressive disorder, using a variant allele of the gene encoding PRODH. Detection of such a variant allele in the genome of a subject may be indicative of the subject's susceptibility to schizophrenia. Furthermore, a variant allele of the PRODH gene can also be used to assay drugs and agents for potential use in treating schizophrenia or a disease or disorder related thereto, such as obsessive compulsive disorder (OCD), bipolar disorder (BP) or major depressive disorder (MDD).
Thus broadly, the present invention extends to an isolated nucleic acid molecule encoding human proline dehydrogenase, wherein the isolated nucleic acid molecule comprises a DNA sequence of SEQ ID NO:1, degenerate variants thereof, fragments thereof, or analogs or derivatives thereof.
Furthermore, the present invention extends to an isolated nucleic acid molecule hybridizable under standard hybridization conditions to the isolated nucleic acid molecule comprising a DNA sequence of SEQ ID NO:1, degenerate variants thereof, fragments thereof, or analogs or derivatives thereof.
The present invention also extends to an isolated nucleic acid molecule comprising a DNA sequence of SEQ ID NO:1, degenerate variants thereof, fragments thereof, or analogs or derivatives thereof, or an isolated nucleic acid molecule hybridzable thereto under standard hybridization conditions, wherein the nucleic acid molecule is detectably labeled. Numerous detectable labels have applications in the present invention. Examples include a radioactive element, such as the isotopes
3
H,
14
C,
32
P, 35S,
36
Cl,
51
Cr,
57
Co,
58
Co,
59
Fe,
90
Y,
125
I,
131
I, and
186
Re, to name only a few, chemicals which fluoresce, or enzymes such as alkaline phosphatase or horseradish peroxidase conjugated to an isolated nucleic acid molecule of the invention.
Moreover, the present invention extends to an isolated nucleic acid molecule comprising a DNA sequence of SEQ ID NO:1, degenerat

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