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Adh7 Nucleotides Adh7-Nukleotide Nucleotides Adh7 (19) & (11) EP 1 090 127 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12N 15/53 (2006.01) C12N 9/04 (2006.01) 28.05.2008 Bulletin 2008/22 C12Q 1/68 (2006.01) C12Q 1/25 (2006.01) A61K 38/44 (2006.01) A61K 48/00 (2006.01) (2006.01) (21) Application number: 99933376.8 A61K 31/07 (22) Date of filing: 23.06.1999 (86) International application number: PCT/SE1999/001136 (87) International publication number: WO 2000/000621 (06.01.2000 Gazette 2000/01) (54) ADH7 NUCLEOTIDES ADH7-NUKLEOTIDE NUCLEOTIDES ADH7 (84) Designated Contracting States: • THE JOURNAL OF BIOLOGICAL CHEMISTRY AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MIRNA ZGOMBIC-KNIGHT: ’Genomic Structure MC NL PT SE and Expression of the ADH7 Gene Encoding Human Class IV Alcohol Dehydrogenase, the (30) Priority: 26.06.1998 SE 9802294 Form Most Efficient for Retinol Metabolism in 26.06.1998 US 90925 P Vitro.’ vol. 270, no. 9, March 1995,, pages 4305 - 4311, XP002919875 (43) Date of publication of application: • PROC NATL ACAD SCI SAMAD TA ET AL: 11.04.2001 Bulletin 2001/15 ’Regulation of dopaminergic pathways by retinoids:activation of the D2 receptor promoter (73) Proprietor: AstraZeneca AB by members of the retinoic acid receptor- retinoid 151 85 Södertälje (SE) X receptor family’ vol. 94, no. 26, December 1997,, pages 14349 - 14354, XP002919876 (72) Inventors: • MOLECULAR ENDOCRINOLOGY ROLF H. • OLSON, Lars ZETTERSTRÖM ET AL: ’Retinoid X Receptor S-181 43 Lidingö (SE) Heterodimerization and Developmental • BÜRVENICH, Silvia Expression Distinguish the Orphan Nuclear S-182 53 Danderyd (SE) ReceptorsNGFI- B,Nurr1,and Nor1’ vol. 10, no. 12, • SYDOW, Olof 1996,, pages 1656 - 1666, XP002919877 S-167 56 Bromma (SE) • PROC. NATL. ACAD. SCI. PETER MCCAFFERY: • ANVRET, Maria ’High levels of a retinoic acid-generating S-175 47 Järfälla (SE) dehydrogenase in the meso-telencephalic • ZHANG, Zhiping dopamine system’ vol. 91, August 1994,, pages S-141 33 Huddinge (SE) 7772 - 7776, XP002919878 • DATABASE EMBL 5 May 1998 (1998-05-05), (56) References cited: SAGE-ONO, K.: "Pharbitis nil PnC401 mRNA for GB-A- 2 292 522 US-A- 5 514 825 leaf protein, comple cds." XPD85101 • DATABASE EMBL 5 May 1998 (1998-05-05), • BIOCHEMICAL AND BIOPHYSICAL RESEARCH SAGE-ONO, K.: "Pharbitis nil PnC401 mRNA for COMMUNICATIONS. HIROKAZU YOKOYAMA ET leaf protein, comple cds." AL: ’Upstream Structure of Human ADH7 Gene and the Organ Distribution of its Expression. ’ vol. 216, no. 1, 1995,, pages 216 - 222, XP002919874 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 090 127 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 090 127 B1 2 Description that there might be another gene in the same locus that might account for the disease. In this case, the synuclein Technical field mutation in the Italian and Greek kindreds may be a mark- er that segregates with the "true" disease gene. [0001] The present invention relates to isolated human 5 [0007] Accordingly, the prior art has not identified any nucleic acids implicated in Parkinson’s disease and the gene responsible for idiopathic Parkinson’s disease in uses thereof, such as in diagnostic and prognostic meth- humans. Thus, in the state of the art, there are still no ods and in pharmaceutical preparations. reliable diagnostic and prognostic tools in this regard and thus, individuals at risk of developing Parkinson’s dis- Background 10 ease have no safe way of knowing this beforehand. In addition, and maybe more importantly, patients suffering [0002] Parkinson’s disease is a neurodegenerative from Parkinson’s disease cannot yet trust the science to disease that strikes men and women alike. It is estimated provide them with a safe remedy of this highly unpleasant that it affects about 15 out of 10.000 individuals and usu- and incapacitating disease. ally it firstappears at anage of about 55-60 years. Despite 15 considerable efforts, the reason for the symptom-causing Summary of the invention degeneration of the midbrain dopamine neurons in pa- tients afflicted by this crippling, non-curable disorder is [0008] The object of the present invention is to fulfill not known. Moreover, while many of the symtoms of Par- the need defined above in regard of Parkinson’s disease. kinson’s disease can be mimicked by lesions or neuro- 20 Accordingly, the present invention conclusively relates toxin administration to experimental animals, the disease to the establishment of the identity of a human gene itself is not known in any other species than man, thus wherein Parkinson’s disease is developped as well as to hampering research aimed at understanding the etiology the specific mutations of said gene associated with the and the development of new therapies. disease. More specifically, the human gene encoding al- [0003] Exposure to toxic compounds in the environ- 25 cohol dehydrogenase 7 (ADH7) has according to the ment remains one hypothetical cause of the disease al- present invention for the first time been shown to be sig- though epidemiological studies have generated few nificant in association with the development of Parkin- clues as to its etiology. More recently, an interest in fa- son’s disease by exhibiting one or more herein defined milial forms of the disease has indicated the presence of mutations triggering the disease. Accordingly, the novel genetic components and linkage to an area on chromo- 30 findings according to the present invention also impli- some 4 has been reported and is discussed in more detail cates a novel use of ADH7 in the diagnosis, treatment below. and/or prevention of Parkinson’s disease. The invention [0004] Thus, in recent linkage studies, autosomal will be disclosed in more detail below together with var- dominant or autosomal recessive types of Parkinson’s ious advantageous novel uses. disease have been mapped to several different loci in 35 the human genome. Although these types of Parkinson’s Brief description of the drawings disease often differ from sporadic Parkinson’s disease and constitute only a small fraction of the total patient [0009] population, the reported loci might confer susceptibility also for idiopatic forms of Parkinson’s disease. 40 Figure 1 shows the previously published sequence [0005] Polymeropoulos et al (Science 274, 1197p. of ADH7 (Zgombic et al., supra). (1996)) mapped autosomal dominant Parkinson to chro- Figure 2 shows the GenBank records U16286 mosome 4q21-q23. They called this area "PARK1". Lat- through 16293 harboring the human ADH7 gene se- er, they found a mutation in the gene for alpha- synuclein quences for the promoter, all exons and intronic se- which segregated with the disease in one large Italian 45 quences in a larger extend than displayed in figure 1. and three Greek kindreds and which they could not find Figure 3 shows Table 1, wherein the primers used in healthy control individuals. Synuclein was found to be to amplify eight fragments of the human ADH7 gene contained abundantly in Lewy bodies, thus providing ev- according to the section "Experimental" below are idence of a causal link between mutation and disease. defined. However, inspite of large efforts by other groups to find 50 Figure 4 shows Table 2, wherein the sequences of synuclein mutations in their own patients, they failed to the eight amplified mutated fragments M1-M7 ac- identify any mutations in the alpha-synuclein gene in their cording to the invention are compared with corre- material. sponding wildtype sections of the sequence dis- [0006] Interestingly, Vaughan et al. (Hum. Mol. Genet. closedin Figure 1 or the GeneBank entriesaccording 7, 751 (1998)) have reported one German family with 55 to Figure 2. autosomal dominant Parkinsonian to show linkage to the Figure 5 shows the localizations of the ADH7 gene PARK1 region 4q21-q23. In this family, no mutations in mutations M1-M7 according to the invention. alpha-synuclein could be identified. Said authors suggest Figure 6A shows Table 3, wherein A1 allele frequen- 2 3 EP 1 090 127 B1 4 cy is disclosed and compared for different groups, the group consisted of M2, M3, and M6, or the wild type while Figure 6B shows Table 4 displaying the oc- sequence corresponding to M1, and at least about 10 curence of homozygotes for A1 and A3 among Par- bases of the adjacent and/or surrounding sequences kinson patients. shown in Figure 4 and also defined by SEQ. ID. NOS. 2, 5 3 and 6 and SEQ. ID. NO. 1, respectively. Said sequenc- Detailed description of the invention es may, in particular embodiments, be surrounded by, or adjacent to, any number of consecutive bases from the [0010] Thus, more specifically, in a first aspect, the wild type human sequence defined in Figure 1, up to es- present invention relates to the use of an alcohol dehy- sentially all of said sequence. For use as a probe, a length drogenase 7 (ADH7) associated nucleic acid, which com- 10 of about 10 bases may be suitable in some methods, but prises parts or all of the nucleotide sequence of the hu- the skilled in this field can easly choose a suitable length man wildtype ADH7 encoding gene, or a variant thereof, depending on the intended use. In one particular embod- including at least one mutation selected from the group iment, the invention relates to an isolated nucleic acid consisting of M2, M3, and M6 as defined in Figure 4.
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