Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
2000-07-11
2003-04-15
Mertz, Prema (Department: 1646)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C530S350000, C435S071100, C435S071200, C435S252300, C435S254110, C435S471000, C435S325000, C435S320100
Reexamination Certificate
active
06548272
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a human novel gene and in particular to a gene for a novel transmembrane protein considered to be a pathogenic gene for bipolar affective disorder.
BACKGROUND ART
Bipolar affective disorder is a disease occurring mainly at an age of about twenty years old, to the middle age and constitutes one of two major endogenous psychoses along with schizophrenia. The center of its mental symptoms is emotional impairment, and this disease is characterized that even after the morbid phase occurs repeatedly during a periodic course, the patient is restored to normal mental conditions without having mental ruin (impaired conditions). The morbid phase includes a manic state showing high emotion and promoted willingness and a depressive state of emotion, and each morbid phase (for a few weeks to a few months) repeatedly appears or both the morbid phases appear alternately, but in some cases the morbid phase may end only once. For treatment of this disease, an anti-depressant or an anti-psychosis medicine is used, and by the advent of lithium salts, chemotherapy has occupied the most important position.
The morbidity risk factor of this disease is estimated to be approximately 0.4% of the population, but in consideration in mild cases not necessitating medical treatment, the morbidity may considerably exceed this figure. The morbidity according to a fact-finding survey conducted in 1963 by the Ministry of Health and Welfare was 0.02%, but naturally this morbidity does not cover non-manifested cases at the time of the survey. In the incidence of this disease, there is a certain difference depending on human race, differentiation and region, and it is noted that the incidence tends to be high in highly differentiated races or in upper classes. It is said that the number of female patients is higher than male patients, but this is necessarily not evident in Japan.
This disease is classified into a unipolar type (type showing the depressive phase only) and a bipolar type (type showing both the phases or the manic phase only), and comparison between the unipolar type and the bipolar type indicates that the incidence of the unipolar type is considerably higher at a ratio of 1:6 to 10. In particular, this trend is significant at the middle age or thereafter.
Diagnosis of bipolar affective disorder is made according to clinical symptoms based on emotional impairment. There is also a report that the level of serotonin or noradrenaline is varied with emotional impairment, and particular attention is paid to the movement of monoamine metabolism-related substances in blood, urine, or cerebrospinal fluid. Further, attention is also paid to impairments in the endocrine functions of the thyroid gland, adrenal cortex etc. and abnormalities in the metabolism of electrolytes affecting the mechanism of neurotransmission, but there is no established method for clinical examination utilizable for diagnosis thereof.
It is considered that a genetic predisposition plays an important role in the onset of bipolar affective disorder. According to a lineage study (empirical hereditary prognosis), the morbidity risk factor of a patient's family is significantly higher than ordinary persons. The morbidity in such a family is estimated to be nearly 10 to 15% and there is no significant difference among patient's brothers, parents and children. According to a recent study, however, bipolar affective disorder is genetically not necessarily a single unit, and the morbidity risk factor of bipolar bipolar affective disorder in the family is genetically higher than that of unipolar depressive insanity in the family, and it is pointed out that generally, in a family of a patient with the bipolar type, the percentage of patients with the bipolar type in the family is relatively high, while in a family of a patient with the unipolar type, the percentage of patients with the unipolar type in the family is relatively high.
In study by a twins method, the involvement of a genetic predisposition is evident, and the morbidity of the disease in both one-egg twins is significantly higher than in both two-egg twins. However, because there is not few exceptional cases, it is considered that the expression of a gene for bipolar affective disorder is considerably affected by the environment as is the case with a gene for schizophrenia [1].
The hereditary mode of bipolar affective disorder, excluding a limited number of families having considerably negative factors in the family, cannot be elucidated in terms of the Mendelian heredity concerned with a single gene, so it is considered that the majority of cases are due to polyfactor-polygene heredity in which a plurality of genes and environmental factors are involved. Further, endogenous factors in bipolar affective disorder, that is, disease-specific changes in organs, biological markers, onset mechanism etc. are not revealed, thus making genetic study further difficult.
In 1987, Egeland et al. reported that there is a strong linkage between chromosome 11q15 HRAS1 and INS genes and bipolar affective disorder [2]. At the same time, in a study where color blindness in the chromosome Xq28 and GP6D were used as markers in a family liable to bipolar impairment, Baron et al. reported that there is a strong linkage thereof to bipolar impairment [3]. However, these and later reports showed some results denying the linkage, and the above study is not an established finding. Besides, regions having a high linkage to bipolar affective disorder include Xq29-27 [4], 4q16 [5], 18q22-23 [6], 18centro [7] and 21q22.3 [8].
However, in the linkage study of bipolar affective disorder, a large number of findings suggesting the linkage are obtained while there are many results denying these findings [9] so that a state of confusion continues. As a result, none of these findings are established, and at present, there is no cloned gene for bipolar affective disorder [10].
DISCLOSURE OF INVENTION
The problem to be solved by the invention is to determine the nucleotide sequence of a pathogenic gene for bipolar affective disorder as well as the amino acid sequence of a protein encoded by said nucleotide sequence.
As a result of their eager study for solving the problem described above, the present inventors isolated a new gene from human chromosome 21q22.3 region and determined its nucleotide sequence. Genes from patients with bipolar affective disorder were amplified by PCR using primers set up on the basis of said nucleotide sequence and analyzed, and as a result it was confirmed that there was a deletion in exon 5 in 10 samples out of 20 samples from patients with bipolar bipolar affective disorder. Accordingly, it is considered that this gene is a pathogenic gene for bipolar affective disorder.
It was revealed that the open reading frame of this gene designated TRPC7 codes for a protein with a molecular weight of 171,217 consisting of 1,503 residues having 7 transmembrane regions. Further, as a result of a search for homology in a database, said protein showed homology with Drosophila TRP (transient receptor potential) protein and human TRP protein as calcium channels.
An object of the present invention is to provide a polypeptide particularly a polypeptide shown in SEQ ID NO:2, which was designated TRPC7 because of its homology with known amino acid sequences such as Drosophila TRP protein and human TRP protein. TRPC7 has seven transmembrane regions similar to other TRPs and is estimated to act as a calcium channel.
A further object of the present invention is to provide a polynucleotide coding for TRPC7, in particular a polynucleotide coding for the polypeptide designated TRPC7 in the present specification. A particularly preferable example of this mode of the present invention is a polynucleotide comprising a region coding for human TRPC7 in the sequence shown in SEQ ID NO:1.
According to this mode of this invention, there are provided isolated nucl
Nagamine Kentaro
Shimizu Nobuyoshi
Eiken Kagaku Kabushiki Kaisya
Fish & Richardson PC
Mertz Prema
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