Primers for screening schizophrenia and a method thereof

Details Primers for screening schizophrenia and a method thereof Primers for screening schizophrenia and a method thereof

2002-03-21

2004-07-20

Horlick, Kenneth R. (Department: 1637)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S091200, C435S091100, C536S023100, C536S024300, C536S024330

Reexamination Certificate

active

06764824

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel primers useful for identifying and screening non-sense mutation with codon TGG coding for amino acid tryptophan substituted with TAG, a non-sense codon, at nucleotide No. 825 in exon 2 of synaptogyrin 1 gene of chromosome 22q11-13. thereby detecting pre-disposition to schizophrenia in a subset of patients and a method thereof.
BACKGROUND AND PRIOR ART REFERENCES
Schizophrenia is a common and devastating illness afflicting at least 1% of the population worldwide. The characteristic symptoms involve disturbances in perception and inference (hallucinations and delusions), abnormalities in language, behaviour and motor function (disorganized speech, bizarre behaviour and catatonia) and deficits in emotional capacity and drive (affective flattening, anhedonia and avolition).
Abnormal neurotransmission affecting the dopamine, serotonin, glutamine, gamma-aminobutyric acid, and cholecystokinin systems have been reported in schizophrenia (Wolf et al, 1993). These abnormalities may affect genes involved in neurotransmitter metabolism, such as Catechol-o-methyl transferase (COMT) (Lachman et al, 1996) and Tyrosine hydroxylase (Ref); neurotransmitter receptors such as dopamine receptors (Seeman et al, 1993), N-methyl-D-Aspartate (NMDA) receptor (Nudmamud et al, 2001) and serotonin receptors (Chiu et al, 2001); and neurotransmitter transporters such as dopamine transporter (Persico et al, 1997).
Neurodevelopmental abnormalities are also strongly implicated in schizophrenia, with reports of defects in neuronal cytoskeleton (Arnold et al, 1991), neuronal cytoarchitecture (Arnold et al, 1997) and migration, cellular polarity, and synaptic pruning (Arnold, 1999). Thus, in schizophrenia, at least two processes appear to be aberrant: neurotransmission and neuronal development primarily affecting the later stages of synapse formation.
Unfortunately, there is no objective laboratory test for schizophrenia, and the diagnosis is made by clinical interview. Since there is a continuing need for developing diagnostic methods and new therapies for such diseases, efforts have been devoted to the characterization and elucidation of the genes responsible for schizophrenia.
In an attempt to device a method for diagnosing schizophrenia, Meloni et al (U.S. Pat. No. 6,210,879) used a microsatellite marker, HUMTH01 present in the first intron of tyrosine hydroxylase gene or finding association with schizophrenia This marker consists of repeated tetrameric TCAT motifs. The most frequently encountered allele of the marker comprises 10 repeated motifs and a deletion of one base pair in the fifth repeated motif, which has the sequence CAT. However, while doing association analysis of this repeat with schizophrenia, they observed that the perfect repeat (without the deletion) was rare and only present in schizophrenic patients.
Although, not much is known about the cause of schizophrenia, the disease has a strong genetic component. Research into the genetics of schizophrenia reveals that this disease is heterogeneous and is a “complex genetic” disease, that is, several genes may be involved in the etiology of this disease.
Several genetic studies have reported significant linkage to several chromosomal regions, which include 1q21-22, 6p24-22, 7q, 8p22-21, 10p14-13, 13q32, 18p and 22q11-13 (Riley and McGuffiin, 2000).
One of the most intensively studied regions amongst these includes several loci on chromosome 22. Initial genome wide scans for schizophrenia by different groups suggested possible linkage for markers on chromosome 22q although neither of the groups reported statistically significant results (Schwab et al, 1999; Coon et al, 1994; Pulver et al, 1994).
A combined transmission disequilibrium and linkage analysis of D22S278 in 574 families further strengthened the possibility of a susceptibility locus on chromosome 22q (Schizophrenia Collaborative Linkage group for chromosome 22). A further line of evidence implicating chromosome 22 in schizophrenia has come from the study of patients with a congenital malformation called Velo Cardio Facial Syndrome (VCFS). VCFS is known to be caused by deletions in the region of 22q11.2-q11.23 and patients suffering from this disorder show a high prevalence of psychiatric illnesses including both bipolar disorder and schizophrenia (Arnold, 2001). Taken together, these independent lines of evidence from cytogenetic studies and linkage analysis studies suggest that chromosome 22 might indeed harbour susceptibility loci for schizophrenia.
Apart from linkage studies, an alternative approach which has evoked a great deal of interest in the recent years has been the study of trinucleotide repeat expansions in bipolar disorder and schizophrenia (Vincent et al, 2000). Studies of anonymous CAG repeats using the Repeat Expansion Detection (RED) technique have demonstrated expanded repeats in schizophrenia and bipolar disorder with considerable overlap between patients and controls (O'Donovan et al, 1996; Morris et al, 1995).
A great deal of effort has focused on the identification of loci containing trinucleotide repeats as candidate genes for these diseases. The candidate gene approach, however, has been unable to demonstrate large expansions of trinucleotide repeats in the range of those seen in tile diseases caused by triplet repeat expansions in patients suffering from schizophrenia and bipolar disorder (Vincent et al, 2000).
The failure to observe large expansions has led to suggestions that it might be worthwhile studying moderate trinucleotide repeat expansions in patients suffering from these diseases (Petronis et al, 1996).
Applicants have also proposed earlier that a difference in allele sizes or ‘allele span’ at such polymorphic trinucleotide repeat loci may also be implicated in bipolar disorder and schizophrenia (Saleem et al, 1998; Saleem et al, 2000).
As chromosome 22 has been repeatedly implicated in bipolar disorder and schizophrenia, susceptibility loci on this chromosome might contain expanded CAG repeats involved in the pathogenesis of these disorders. In order to identify such loci on chromosome 22, CAG repeals containing more than five repeats and mapping to schizophrenia susceptibility loci on chromosome 22 were identified and studied for the association with the disease. One of such CAG repeat markers, 22CH3, present on chromosome 22q11-13 was shown to be associated with schizophrenia in Indian population (Saleem et al, 2001). This locus is biallelic with 7 and 8 CAG repeats. The 8 repeat allele at this locus was significantly over represented in schizophrenic patients when compared to ethnically matched controls. The applicants further identified genes in the vicinity of this locus. Out of these, Synaptogyrin1 was chosen as a candidate gene for schizophrenia since it plays an integral role in neurotransmitter release, thus, mutations in this gene could explain many of the defects observed in schizophrenia.
Two recent studies have reported mutations in two different genes in schizophrenic patients. One of them is a frameshift mutation in KCNN3 gene, located on chromosome 1q21-22, Sound in only one schizophrenic patient (Bowen et al, 2001). The mutation found to be associated with schizophrenia is a missense mutation in WKL 1 gene, present on 22q11-13, and is shown to be segregating with schizophrenia in only one large family (Meyer et al, 2001). Since schizophrenia is a multigenic disorder, so it is quite possible that this region may harbour some other genes also, which when mutated might lead to schizophrenia.
In a study involving microarray expression profiling of prefrontal cortex from matched pairs of patients with schizophrenia and control subjects, it was found that transcripts encoding proteins involved in the regulation of presynaptic function were decreased in all subjects with schizophrenia (Mimics, 2000).
Further Double knockout mice for Synaptogyrin 1 and synaptophysin genes have shown deficits in long-term and short-term synaptic plasticity (Roger et al, 1999). These studies onl

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