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WO1999006539A1 - Nouveaux peptides zggbp1 associes au trouble affectif bipolaire du type 1, sequences et utilisations de ces derniers - Google Patents

Nouveaux peptides zggbp1 associes au trouble affectif bipolaire du type 1, sequences et utilisations de ces derniers Download PDF

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Publication number
WO1999006539A1
WO1999006539A1 PCT/GB1998/002259 GB9802259W WO9906539A1 WO 1999006539 A1 WO1999006539 A1 WO 1999006539A1 GB 9802259 W GB9802259 W GB 9802259W WO 9906539 A1 WO9906539 A1 WO 9906539A1
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WO
WIPO (PCT)
Prior art keywords
zggbpl
polynucleotide
protein
seq
gene
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PCT/GB1998/002259
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English (en)
Inventor
Angela Veronica Flannery
Maria Christina Martina Finnegan
Original Assignee
Zeneca Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zeneca Limited filed Critical Zeneca Limited
Priority to EP98936528A priority Critical patent/EP0996716A1/fr
Priority to JP2000505281A priority patent/JP2001512007A/ja
Publication of WO1999006539A1 publication Critical patent/WO1999006539A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/93—Ligases (6)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • This invention relates to a novel human gene (ZGGBPl) associated with affective neurological disorders such as bipolar affective disorder.
  • ZGGBPl novel human gene
  • the invention also relates to homologues of the ZGGBPl gene in species such as rat and mouse useful in providing animal models of affective disorders.
  • the invention further relates to both the cDNA and the structural gene and to fragments encoding functional domains within the gene.
  • the invention also relates to means for producing the protein encoded by the gene and to means for regulating its production and activity in vivo.
  • Affective disorders comprise a broad and heterogeneous category of psychiatric illness with a prevalence of up to 20% in the population. The most severe of these disorders is bipolar type I which affects approximately 1 % of the population and this rate is fairly consistent across countries.
  • the disease affects young adults, with a mean age of onset of 22 years. Treatment depends upon the phase of the disease and pharmacological agents include lithium carbonate, carbamazepine or valproic acid, tricyclic antidepressants. Monoamine oxidase inhibitors and selective serotonin re-uptake inhibitors are now also being used. The success rate of individual drugs is variable and some patients are treated with a combination of agents, although most have some unwanted side-effects. At present the precise diagnosis of individual affective disorders is difficult and new, gene based, diagnostic methods are desirable.
  • Ned-4 is the human homologue of the mouse nedd-4 gene which is known to be differentially expressed during neural development and to be involved in signal transduction. Human ned-4 has been shown (Schild et al. 1996, Straub et al. 1996) to be a negative regulator of a sodium channel which is deleted in Liddle's syndrome (a hereditary form of hypertension).
  • Nedd-4 was originally isolated as a partial cDNA clone from a mouse brain library (Kumar et al. 1992) as one of a set of genes which were differentially expressed during development (Neural precursor cells expressed developmentally down-regulated).
  • the derived amino acid sequence contains three copies of the WW domain (Andre & Springael 1994, Bork & Sudol, 1994; Hofmann & Boucher, 1995), a Ca lipid binding (CaLB/C2) domain (Brose et al. 1995) and a Hect (homologous to the E6-AP carbodyl terminus) domain which has homology to a ubiquitin ligase (E3) enzyme (Huibregtse et al. 1995).
  • E3 ubiquitin ligase
  • Ned-4 The human homologue of nedd-4 (Ned-4) was isolated as an randomly cloned EST (KIAA0093) from immature myeloblast mRNA (Nomura et al. 1994) and shown by sequence comparison to have 86% identity at the amino acid level to the mouse sequence. The human sequence, however, has a fourth copy of the WW domain.
  • the WW domain is a 40 amino acid sequence found in several unrelated proteins. The two highly conserved tryptophans give it its name. The function of the domain is thought to be involved in protein-protein interactions. Despite their functional diversity, the proteins listed all appear to be involved in cell signalling or regulation. It has been shown that the WW domains of Nedd-4 interact with the proline-rich PY motifs in the epithelial sodium channel in the kidney (Schild et al. 1996). Mutational deletion of the PY motifs in the epithelium sodium channel in Liddle's syndrome, an inherited disease causing systemic hypertension characterised by hyperactivity of the sodium channel, has been shown to abrogate binding of Nedd-4 (Straub et al. 1996). It is therefore likely that Nedd-4 has a negative regulatory role when bound to the channel.
  • the Hect domain is an E3 ubiquitin-protein ligase domain and enzymes with this domain catalyse polyubiquitination, which is involved in several cellular processes including proteolytic degradation.
  • the CaLB/C2 domain is thought to be involved in calcium-dependent phospholipid binding, although some proteins containing this domain do not bind calcium and other putative functions for the C2 domain such as binding to inositol -1,3,4,5-tetraphosphate have been suggested. Examples of proteins containing this domain are Protein Kinase C (PKC) isoenzymes and synaptogamins.
  • PKC Protein Kinase C
  • PCT patent application W097/ 12962 discloses a protein (Pub3) with homology to Publ, a Schizosaccaromyces Pombe protein which has an apparent function in the ubiquitination of, among other cellular proteins, the mitotic activating tyrosine phosphatase cdc25 and the tumour suppresser protein p53. As such this protein may be involved in regulating the progression of proliferation in eukaryotic cells by effectively controlling the activity of the cdk complexes by modulating the availability of cdc25 and/or p53
  • a comparison of Pub3 with ZGGBPl revealed that the sequences represent two distinct genes which code for two separate, structurally unrelated proteins.
  • the two genes share sequence homology within a certain defined region, the sequences are identical within the region 516-3568 of ZGGBPl, but they do not show any homology within the regions 5' and 3 'of this sequence.
  • the derived amino acid sequence for ZGGBPl is completely different to that derived for Pub 3 as both have been initiated from a different start methionine.
  • a comparison of the nucleotide sequences for ZGGBPl and Pub 3 is outlined in Figure 5.
  • the ZGGBPl gene having the full length cDNA as set out in SEQ ID NO: 1.
  • fragments we mean contiguous regions of the gene including complementary DNA and RNA sequences, starting with short sequences useful as probes or primers of say about 8-50 bases, such as 10-30 bases or 15-35 bases, to longer sequences of up to 50, 100, 200, 500 or 1000 bases.
  • any convenient fragment of the gene of say up to 2kb, 3kb, 4kb or more than 4kb may be a useful gene fragment for further research, therapeutic or diagnostic purposes.
  • Further convenient fragments include those whose terminii are defined by restriction sites within the gene of one or more kinds, such as any combination of Rsal, Alul and Hinfl.
  • homologues of the ZGGBPl gene in species such as rat and mouse useful in providing animal models of affective disorders.
  • homologue we mean a corresponding ZGGBPl gene in another species, which displays greater than 85% sequence homology, conveniently greater than 90%, for example 95%, to the human ZGGBPl sequence.
  • the full sequences of the individual homologues may be determined using conventional techniques such as hybridisation, PCR and sequencing techniques, starting with any convenient part of the sequence set out in SEQ ID NO: 1.
  • the partial sequence of the mouse gene is set out in SEQ ID NO: 3 and this gene and the protein encoded by this gene represent further independent aspects of the invention.
  • polynucleotide sequences capable of specifically hybridising to the ZGGBPl gene.
  • specifically hybridising we mean that the polynucleotide hybridises under stringent conditions to the sequence on chromosome 18q21 as set out in SEQ ID No: 1, or to the corresponding non-coding sequence, to the exclusion of other genomic loci.
  • a species such as a peptide nucleic acid may be an acceptable equivalent to a polynucleotide, at least for purposes that do not require translation into protein.
  • a recombinant ZGGBPl protein obtained by expression of all or a part of the cDNA as set out in SEQ ID NO: 1.
  • the recombinant protein may comprise all or a convenient part of the peptide sequence set out in SEQ ID NO: 2.
  • the production of a protein according to the invention may be achieved using standard recombinant DNA techniques involving the expression of the protein by a host cell as described for example by Sambrook et al. 1989.
  • the isolated nucleic acids described herein may for example be introduced into any convenient expression vector for example the T7 Studier system for expression in E.coli (US-A-4952496), Pichia pastoris for expression in yeast, the Baculovirus system for expression in insect cells and the GS system for expression in mammalian cells by operatively linking the DNA to any necessary expression control elements therein and transforming any suitable prokaryotic or eukaryotic host cell with the vector using well known procedures.
  • any convenient expression vector for example the T7 Studier system for expression in E.coli (US-A-4952496), Pichia pastoris for expression in yeast, the Baculovirus system for expression in insect cells and the GS system for expression in mammalian cells by operatively linking the DNA to any necessary expression control elements therein and transforming any suitable prokaryotic or eukaryotic host cell with the vector using well known procedures.
  • the invention further extends to cells containing said recombinant plasmids and to a process for producing a ZGGBPl protein of the invention which comprises culturing said cells such that the desired protein is expressed and recovering the protein from the culture.
  • a process for producing a ZGGBPl protein of the invention which comprises culturing said cells such that the desired protein is expressed and recovering the protein from the culture.
  • the nucleotide sequence in SEQ ID NO: 1 is inserted downstream of the SV40 promoter in the pGEX plasmid vector, and either transiently or stably expressed in COS -7 cells. Expression of the protein according to the invention can be detected following disruption of the cells by Western blotting .
  • the nucleotide sequence in SEQ ID NO: 1 is inserted downstream of the S V40 promoter and the glutathione-S-transferase (GST) coding sequence in the pBC plasmid vector, and either transiently or stably expressed in COS -7 cells allowing expression of the corresponding fusion protein.
  • GST glutathione-S-transferase
  • Expression of the fusion protein can be detected following disruption of the cells by Western blotting with antibodies to GST, and furthermore the fusion protein can be used in an affinity binding procedure to find proteins which are functional partners of the protein of the invention from cell extracts.
  • a ZGGBPl protein of the invention may in particular be used to screen for compounds which regulate the activity of the enzymes and the invention extends to such a screen and to the use of compounds obtainable therefrom to regulate the activity of the protein in vivo.
  • a method for identifying a compound capable of modulating the action of a ZGGBPl protein comprises subjecting one or more test compounds to a screen comprising (A) a protein containing the amino acid sequence shown in SEQ ID NO: 2 or a homologue or fragment thereof, or (B) the nucleotide sequence shown in SEQ ID NO: 1 or a homologue or fragment thereof, or (C) a host cell expressing a ZGGBPl polypeptide or a homologue or fragment thereof.
  • the screen according to the invention may be operated using conventional procedures, for example by bringing the test compound or compounds to be screened and an appropriate substrate into contact with the protein or a cell capable of producing it and determining affinity for the protein in accordance with conventional procedures.
  • any compound identified in this way may be used in the treatment of humans and/or other animals of one or more of the above mentioned diseases.
  • the invention thus extends to a compound selected through its ability to regulate the activity of the protein in vivo as primarily determined in a screening assay utilising the protein containing an amino acid sequence shown in SEQ ID NO: 2 or a homologue or fragment thereof, or a gene coding therefor for use in the treatment of a disease in which the over- or under-activity or unregulated activity of the protein is implicated.
  • the ZGGBPl gene of the invention may also be used as the basis for diagnosis, for example to determine expression levels in a human subject, by for example direct DNA sequence comparison or DNA/RNA hybridisation assays. Diagnostic assays may involve the use of nucleic acid amplification technology such as the PCR and in particular the Amplification Refractory Mutation System (ARMS) as claimed in our European Patent No. 0 332 435. Such assays may be used to determine allelic variants of the gene, for example insertions, deletions and/or mutations such as one or more point mutations. Such variants may be heterozygous or homozygous.
  • amplification primers may be provided for use in the above diagnostic methods. In general, these are provided as a set and used for PCR amplification. One of the primers conveniently hybridises to a ZGGBPl locus outside the region defined by base pairs 516-3568 thus allowing the ZGGBPl gene on 18q21 to be identified to the exclusion of other loci.
  • the ZGGBPl gene may also be used in gene therapy, for example where it is desired to modify the production of the protein in vivo, and the invention extends to such uses.
  • Knowledge of the gene according to the invention also provides the ability to regulate its expression in vivo by for example the use of antisense DNA or RNA.
  • an antisense DNA or an antisense RNA which is complementary to the polynucleotide sequence shown in SEQ ID NO: 1.
  • complementary we mean that the two molecules can base pair to form a double stranded molecule.
  • the antisense DNA or RNA for co-operation with the gene in SEQ ID NO: 1 can be produced using conventional means, by standard molecular biology and/or by chemical synthesis as described above.
  • the antisense DNA or antisense RNA may be chemically modified so as to prevent degradation in vivo or to facilitate passage through a cell membrane and/or a substance capable of inactivating mRNA, for example ribozyme, may be linked thereto and the invention extends to such constructs.
  • the antisense DNA or antisense RNA may be of use in the treatment of diseases or disorders in humans in which the over- or under-regulated production of the gene product has been implicated.
  • diseases or disorders may include those described under the general headings of neurologic, eg. stroke, dementia, renal eg. hypertension, nephrosis, cardiovascular disorders.
  • Convenient DNA sequences may be obtained using conventional molecular biology procedures, for example by probing a human genomic or cDNA library with one or more labelled oligonucleotide probes containing 10 or more contiguous nucleotides designed using the nucleotide sequences described here.
  • pairs of oligonucleotides one of which is homologous to the sense strand and one to the antisense strand, designed using the nucleotide sequences described here to flank a specific region of DNA may be used to amplify that DNA from a cDNA library.
  • the ZGGBPl protein of the invention and homologues or fragments thereof may be used to generate substances which selectively bind to it and in so doing regulate the activity of the protein.
  • substances include, for example, antibodies, and the invention extends in particular to an antibody which is capable of recognising one or more epitopes containing the protein binding domains shown in Figure 1.
  • the antibody may be neutralising antibody.
  • antibody is to be understood to mean a whole antibody or a fragment thereof, for example a F(ab)2, Fab, FV,. VH or VK fragment, a single chain antibody, a multimeric monospecific antibody or fragment thereof, or a bi- or multi- specific antibody or fragment thereof.
  • Figure 1 shows the predicted amino acid sequence of ZGGBPl.
  • the C2 domain is indicated by carets
  • the four WW domains are indicated by asterisks
  • the Hect domain is indicated by underlining .
  • Figure 2 shows a comparison of amino acid sequences of human ned4 Swissprot entry
  • Figure 3 shows a Northern blot analysis of various human tissues probed with ZGGBPl.
  • Figure 4 shows a comparison of the nucleic acid sequences of human and mouse ZZGBPl.
  • the mouse sequence is a partial cDNA which spans the C-terminal portion of the human protein coding region.
  • Figure 5 shows a comparison of the nucleic acid sequences for ZGGBPl and Pub3
  • Figure 6 shows a polymorphism located at position 3554 of the cDNA sequence
  • Figure 7 shows a polymorphism located at position 4828 of the cDNA sequence
  • Figure 8 shows a polymo ⁇ hism located in an intronic sequence derived from a BAC containing ZGGBPl
  • Figure 9 shows a variable number of tetranucleotide repeats located within an intronic sequence from ZGGBPl
  • Figure 10 shows an insertion at position 4032 of the cDNA sequence
  • the 18q21 region described by Stine et al. (1995) is delimited by the STS markers used by that group to identify linkage. They found the most strongly linked marker to be D18S41, which had a LOD score of 3.51 in cases of paternal inheritance. Linkage declined over flanking markers.
  • YACs Yeast Artificial Chromosomes
  • DNA from the YACs was prepared and used in a PCR-based hybridisation approach to enrich for transcripts from a human fetal brain cDNA library. This approach, known as direct selection (Lovett et al. 1991) has been shown to be efficient in identifying transcripts present on large genomic clones.
  • the UNIGENE database is a repository for transcripts which have been mapped by taking representative Expressed Sequence Tagged Sites (ESTs) and performing PCR analysis on a panel of radiation hybrids which have been calibrated with respect to a framework of 1000 genetic markers (Schuler et al. 1996). We found 36 EST clusters which had been mapped to a radiation hybrid map interval which corresponded to the 18q21 region of interest and to flanking regions outside.
  • ESTs Expressed Sequence Tagged Sites
  • FISH Fluorescence In Situ Hybridisation
  • Oligonucleotide primers specific to ZGGBPl were used in combination with vector specific primers to amplify DNA across the unknown part of the gene. Since the distance to be covered was unknown, we performed long PCR using the commercially available BCL Expand enzyme and long (30mer) oligonucleotide primers. Since we were using unamplified material, where our target cDNAs were likely to be present only in very small amounts, we utilised a secondary PCR step with nested oligonucleotide primers and again using long PCR to yield sufficient PCR products to be visible by gel analysis and also to minimise the possibility of non-specific PCR amplification. The PCR products derived from these experiments were then purified and sequenced directly.
  • DNA sequence obtained was used to design further primers to walk along the gene in a 3' - 5' direction.
  • the complete nucleotide sequence derived from this work is 5.2kb and the translated amino acid sequence is shown in SEQ ID NO: 1.
  • the amino acid sequence derived from the cDNA was compared with that of ned-4 and is shown in Figure 2.
  • the proteins diverge markedly towards the N-terminal portion of the protein, although there is conservation of the common functional motifs.
  • BAC Bacterial Artificial Chromosome
  • the full length sequence of ZGGBPl shown in SEQ ID NO: 1 was used to search the dbEST database to identify homologous mouse sequences.
  • Three overlapping IMAGE clones were identified (IMAGE I.D.479436, 573510, 482922) comprising a partial transcript.
  • Comparison of the mouse and human nucleotide sequence is shown in Figure 4.
  • the mouse clones were isolated for use as a probe for in situ hybridisation on sections of mouse brain during development, and as a probe of mouse genomic libraries to isolate genomic clones and to produce transgenic mice by gene targeting using homologous recombination.

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Abstract

On décrit un nouveau gène humain (ZGGBP1) qui est associé aux troubles neurologiques affectifs tels que la maladie affective bipolaire. On décrit un ADNc entier codant le gène humain ZGGBP1, un ANDc partiel codant le gène ZGGBP1 de souris, ainsi que des variants polymorphes du gène et les domaines fonctionnels codés dans le gène. Cette invention concerne également des procédés permettant d'identifier des composés qui modulent l'activité de la protéine ZGGBP1 et des dosages de diagnostic qui permettent de détecter ZGGBP1 dans des prélèvements biologiques.
PCT/GB1998/002259 1997-08-01 1998-07-28 Nouveaux peptides zggbp1 associes au trouble affectif bipolaire du type 1, sequences et utilisations de ces derniers WO1999006539A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP98936528A EP0996716A1 (fr) 1997-08-01 1998-07-28 Nouveaux peptides zggbp1 associes au trouble affectif bipolaire du type 1, sequences et utilisations de ces derniers
JP2000505281A JP2001512007A (ja) 1997-08-01 1998-07-28 Ｚｇｇｂｐ１、１型双極性感情障害に関与する新規ペプチド、配列及びその使用

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GBGB9716162.4A GB9716162D0 (en) 1997-08-01 1997-08-01 Novel compounds
GB9716162.4 1997-08-01

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005024024A1 (fr) * 2003-09-10 2005-03-17 Bionomics Limited Mutations dans la famille des genes nedd4 impliquees dans l'epilepsie et autres troubles du snc
US6897022B2 (en) 1996-03-29 2005-05-24 University Of Miami Susceptability and resistance genes for bipolar affective disorder

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009136444A1 (fr) * 2008-05-09 2009-11-12 カルナバイオサイエンス株式会社 Procédé de criblage d’agent de prévention ou de traitement de trouble bipolaire de type i

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037223A1 (fr) * 1996-04-03 1997-10-09 Cytogen Corporation Identification et isolement de nouveaux polypeptides ayant des domaines ww et procedes d'utilisation

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US6001619A (en) * 1995-10-04 1999-12-14 Cold Spring Harbor Laboratory Ubiquitin ligases, and uses related thereto

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WO1997037223A1 (fr) * 1996-04-03 1997-10-09 Cytogen Corporation Identification et isolement de nouveaux polypeptides ayant des domaines ww et procedes d'utilisation

Non-Patent Citations (3)

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Title
MORS O. ET AL.: "Cytogenetic abnormalities on chromosome 18 associated with bipolar affective disorder or schizophrenia", BRITISH JOURNAL OF PSYCHIATRY, vol. 170, March 1997 (1997-03-01), GB, pages 278 - 280, XP002087611 *
OHARA O. ET AL.: "Prediction of the sequences of unidentified human genes. VIII. The complete senquences of 77 new cDNA clones from brain which can code for large proteins in vitro", EMBL DATABASE, 5 December 1997 (1997-12-05), HEIDELBERG, DE, XP002087609 *
STINE O.C. ET AL.: "Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect", AMERICAN JOURNAL OF HUMAN GENETICS, vol. 57, no. 6, 1995, US, pages 1384 - 1394, XP002087610 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6897022B2 (en) 1996-03-29 2005-05-24 University Of Miami Susceptability and resistance genes for bipolar affective disorder
WO2005024024A1 (fr) * 2003-09-10 2005-03-17 Bionomics Limited Mutations dans la famille des genes nedd4 impliquees dans l'epilepsie et autres troubles du snc

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