Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1998-09-03
2000-12-26
Clark, Deborah J.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
536 231, 536 235, C12Q 108, C07H 2102, C07H 2104
Patent
active
061657166
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a method of screening for and for diagnosis of psychiatric disorders and other disorders of serotonergic function, for example migraine.
Serotonin (5-hydroxytryptamine or 5-HT) is known to be involved in brain function and activity. The serotonin transporter (also known as 5-HTT) has been targeted using highly selective drugs to effectively treat depressive illness and anxiety disorders (see Anderson et al, J Psychopharmacol 1994 8; 238-249).
The structure of the rat serotonin transporter cDNA was published in 1991 (Blakely et al, Nature 1991 354, 66-70; and Hoffman et al, Science 1991 254, 578-580) and U.S. Pat. No. 5,418,162 is directed to the sequence of the cDNA for the rat serotonin transporter and its use as an oligonucleotide probe which could be used as a PCR extension primer. The corresponding human cDNA was reported by Lesch et al, Journal of Neural Transmission 91; 68-73 1993 and separately by Ramamoorthy et al, in Proceedings of the National Academy of Sciences, USA, 19; 2542-2546 1993.
The structure and arrangement of the human serotonin transporter gene was first published in 1994 by Lesch et al (Journal of Neural Transmission 95; 157-162). The authors noted the existence of a "17 bp repetitive element" as a variable number tandem repeat (VNTR) which occurred in the second intron of the gene. The sequence data for the VNTR is available in the Genbank/EMBL databases under accession number X76754 and is reproduced as part of FIG. 1. Lesch et al noted that the majority of the chromosomes examined had either 10 or 11 copies of the repeat and for such samples the frequency of the 10 VNTR sequence was 0.47 with 41% of individuals displaying heterogeneity. It was speculated that the number of repeats could possibly play a role in the pathogenesis of neuropsychiatric illness. To date no evidence has been reported which definitively links the VNTR sequences with any particular function.
The human serotonin transporter gene is localised to chromosome 17q11.1-q12 (see Ramamoorthy et al 1993 supra) and to date there is no published evidence for genetic linkage of any affective disorder to this part of the genome. Current data indicates that, while there is a genetic basis for psychiatric disorders such as anxiety and depression, and also for migraine, there is no evidence which convincingly demonstrates an underlying molecular basis for genetic susceptibility in either case.
For example, a study made by Lesch et al in 1995 (Biological Psychiatry 37; 215-223) in which 17 patients suffering from major depressive or bipolar disorder were screened for mutations in the serotonin transporter cDNA sequence showed no difference compared to the four controls.
The studies leading to the present invention have surprisingly found 3 alleles of the VNTR region in intron 2 of the serotonin transporter gene. The 3 alleles located are all novel and are designated STin2.9, STin2.10 and STin 2.12 containing 9, 10 and 12 copies of the VNTR repeat, respectively. The third allele (STin 2.10) containing 10 copies of the repeat differs from that described previously by Lesch et al (1994, supra). No individuals possessing 11 copies of the repeat were identified.
The frequencies of the different allele forms were compared between the control group and groups having a major affective disorder. There was a significant difference between the control and affective disorder groups. In particular the presence of the STin2.9 allele was found to be significantly associated with affective disorder and was most common in unipolar patients. This is the first time that a genetic variation at the level of DNA sequence in a candidate gene has been positively associated with affective disorders.
Thus, the present invention provides the novel alleles STin2.9, STin2.10 and STin2.12. The sequence of each of the alleles STin2.9, STin2.10 and STin2.12 are presented in FIG. 1, labelled accordingly and compared to the 10 repeat sequence reported by Lesch et al, 1994, supra. The present invention also provides a polynuc
REFERENCES:
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Published by American Psychiatric Association, Washington D.C. p. 317-318, 1994.
Parsian et al., American Journal of Medical Genetics, vol. 54(1), p. 5-7, Mar. 1994.
Ogilvie et al., "Polymorphism in serotonin transporter gene associated with susceptibility to major depression", Lancet, vol. 347, Mar. 16, 1996, pp. 731-733.
Collier et al., "The serotonin transporter is a potential susceptibility factor for bipolar affective disorder", Neuroreport, vol. 7, No. 10, Jul. 8, 1996, pp. 1675-1679.
Lesch et al., "Organization of the human serotonin transporter gene", Journal of Neural Transmission, vol. 95, 1994, pp. 157-162.
Battersby Sharon
Fink George
Goodwin Guy Manning
Harmar Anthony John
Ogilvie Alan David
Chen Shin-Lin
Clark Deborah J.
Medical Research Council
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