WO1998056950A1 - Sequences d'adn riches en triplet repete utiles dans le diagnostic de maladies a repetition trinucleotidique - Google Patents
Sequences d'adn riches en triplet repete utiles dans le diagnostic de maladies a repetition trinucleotidique Download PDFInfo
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- WO1998056950A1 WO1998056950A1 PCT/FR1998/001187 FR9801187W WO9856950A1 WO 1998056950 A1 WO1998056950 A1 WO 1998056950A1 FR 9801187 W FR9801187 W FR 9801187W WO 9856950 A1 WO9856950 A1 WO 9856950A1
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Definitions
- the present invention relates to the detection of human genes comprising sequences with repeated triplets CAG / CTG or CGG / GCC, as well as the use of these genes in the diagnosis and the possible treatment of certain monogenic diseases or polygenic diseases with component hereditary.
- the abnormal polymorphism of CAG / CTG or CGG / GCC repeating triplet sequences is a mutation involved in at least ten inherited human diseases (called repeating triplet diseases) that are primarily, but not exclusively, neurodegenerative diseases.
- the expansion (several supernumerary triplets in patients) of repeated CAG / CTG triplet sequences is involved in particular in spinobulbar atrophy (SBMA), myotonic dystrophy (DM), spinocerebellar ataxia (SCA1) SCA1, SCA2, SCA3 , and SCA6, dendato-rubro-pallydoluysiane atrophy (DRPLA), and Huntington's disease (1 to 3).
- SBMA spinobulbar atrophy
- DM myotonic dystrophy
- SCA1 spinocerebellar ataxia
- SCA1 dendato-rubro-pallydoluysiane atrophy
- DRPLA dendato-rubr
- CGG / GCC repeat triplet sequences are notably implicated in fragile X syndrome (1).
- restricted polymorphism of sequences with a repeated CAG / CTG triplet is notably implicated in Behçet's disease, an autoimmune disease for which the passage of 5 to 6 GCT codons coding for a polyalanine is associated with the disease (4).
- CAG / CTG or CGG / GCC also called dynamic mutation
- the expansion of CAG / CTG or CGG / GCC is often associated with a phenomenon of anticipation, the size of the repetitions often being inversely correlated with the age of onset and / or the severity of symptoms.
- the expansion of the CAG / CTG repeats can appear in the non-coding (DM) or coding regions (for example SBMA, HD, DRPLA, SCAs) of the transcripts. These transcripts are sometimes expressed in tissues other than the brain and when they are translated lead to products of larger genes and carrying an abnormally elongated polyglutamine domain (1 to 3).
- the expansion of repeated CAG / CTG triplets can be very large (for example DM; several hundred triplets), moderate (for example HD or SCA1; in general more than 35 triplets), or even very moderate (for example SCA6; in general less than 35 triples). In the normal state, these repetitions can be highly polymorphic
- a variation of a single triplet within a short, weakly polymo ⁇ hical repeated triplet can also cause disease (4).
- Autism and familial dementia which show variability in the age of onset or in the severity of symptoms, could also be caused by dynamic mutations.
- a fairly large number of diseases could also originate or involve dynamic mutations: Parkinson's disease, spastic paraplegias, cerebrospinal ataxias not previously listed, - zonular cataracts, uncontrollable tremors, familial amyloid neuropathies, granulomatous arthritis familial (Blau's disease), hemifacial microsomies, - certain anemias and glaucomas, obsessive-compulsive disorders. • The above demonstrates the considerable importance of repeated triplets for the diagnosis and treatment of several diseases.
- the present invention is based on a systematic study of the CAG / CTG or CGG / GCC repeats (which will be designated below by "[CAG] n" and “[CGG] n” respectively, n being the number of repetitions of the triplet), this study having been carried out with human cDNA libraries, these having undergone a first general screening, then the selected sequences having been selected on the basis of a certain number of criteria making it possible to ensure that the sequences in question belonged to new human genes and could, with high probability, be implicated in repeated triplet diseases. Finally, the selected sequences were the subject of a more complete study intended to allow their localization.
- cDNA from human brains were studied to analyze the presence of CAG repeats using the hybridization of oligonucleotides on high density membranes.
- the two libraries were obtained from mRNAs using the oligo-dT primer, one of the libraries being made up of fetal brain (FB) cDNA clones and the other library being made up of clones of Normalized newborn brain cDNA (NIB).
- FB fetal brain
- NBI Normalized newborn brain cDNA
- the present invention is based on the demonstration of certain sequences capable of being involved in repeated triplet diseases obtained under hybridization conditions making it possible to select cDNAs which contain a number of [CAG] or [ CGG] greater than 7, which are more likely to be polymorphous in a sick population.
- the complete conditions for analysis and selection of these different sequences will not be detailed below, only the elements making it possible to locate and re-isolate them will be provided, in particular, using the PCR primers which will be described below.
- the present invention relates to a transcribed DNA sequence rich in repetitive triplet CAG / CTG or CGG / GCC corresponding to sequences A to L of the table, as well as their normal and mutated alleles and the complementary sequences.
- normal alleles is meant the alleles as they have been isolated or as they can be isolated from samples of normal individuals, the “mutated alleles” being the alleles of the genes carrying the sequences [CAG] n or [CGG] n abnormally repeated.
- sequences in question are for the first time identified as being part of a gene which may have a mutation, said genes not having, moreover, in themselves never been described.
- the highlighted sequences show very variable percentages of heterozygosity (HTZ) ranging from 0 to 0.75%.
- these sequences are identified in the table and can, if necessary, be isolated using the following primers: SEQ ED 1 to 24, primers 1 to 24 corresponding, in pairs, to sequences A to L mentioned above.
- sequences thus highlighted can, first of all, be used within the framework of the diagnosis, and more exactly of a prognosis. Indeed, like a large number of diseases having a genetic support, the demonstration of the presence of a sequence presenting an abnormal number of repetitions of triplet [CAG] n or [CGG] n cannot in itself ensure the occurrence of the disease, but must be interpreted according to a set of other information to allow either a very early diagnosis or possibly specific surveillance, especially in families at risk.
- This diagnosis can be made by comparing the DNA sequence according to the patient's invention with a normal sequence to detect the presence of additional trinucleotide repeats. More particularly, the present invention relates to a method of highlighting the risks of the appearance of a disease trinucleotide repeat in a patient, characterized in that the DNA sequence according to the invention of said patient is compared to a normal sequence to detect the presence of additional trinucleotide repeats.
- primers which can be used in the context of the methods according to the invention, mention should be made of the primers of SEQ IDs 1 to 24 which constitute pairs of primers for each of the sequences which are the subject of the invention.
- sequences according to the present invention are amplified and it is then possible, by comparison with a normal and / or standard sample, to demonstrate the presence of the supernumerary triplets and therefore the possibility of occurrence of a disease linked to this type of dynamic mutation.
- the present invention also relates to genes and their alleles which carry, at least in part, these sequences, said genes being, of course, directly involved in the occurrence of the disease. It also relates to a transformed cell expressing all or part of the above genes, a protein obtained from such a cell, a protein interacting with the aforementioned protein as well as a vector expressing one of these proteins.
- the corresponding genes can be expressed in cells by known means in order to produce the corresponding proteins.
- these proteins being involved in the disease, we will wish to reduce their quantity, either by blocking their expression by appropriate methods at the level of genes or regulatory elements, or by fixing or inactivating them, for example by using receptor proteins acting as decoys. Again, these receptor or inactivated proteins can be generated in situ by expression of the corresponding DNA sequences.
- the second library contains 40,128 normalized cDNAs of newborn brains (NIB clones) subcloned into a lafmid vector (6) which is part of the resources of the IMAGE consortium
- [CAG] n or [CGG] n perfect, but also the complex [CAG] n or [CGG] n sequences, that is to say those which are punctuated by insertions of triplets; indeed, this presence of inserted triples is observed in particular in the case of SCA1, while such is not the case for SBMA, MD and HD.
- the new clones selected from NIB libraries are distinct from those selected from the FB group. This is in keeping with the fact that the human brain expresses a large number of distinct genes at different stages of development. Finally, from the present observations, it appears that [CAG] n or [CGG] n sequences are rare in human cDNAs representative of the 3 ′ regions of the mRNAs.
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP98929536A EP0988399A1 (fr) | 1997-06-11 | 1998-06-10 | Sequences d'adn riches en triplet repete utiles dans le diagnostic de maladies a repetition trinucleotidique |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR97/07225 | 1997-06-11 | ||
FR9707225A FR2764611B1 (fr) | 1997-06-11 | 1997-06-11 | Sequences d'adn riches en triplet repete utiles dans le diagnostic de maladies a repetition trinucleotidique |
Publications (1)
Publication Number | Publication Date |
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WO1998056950A1 true WO1998056950A1 (fr) | 1998-12-17 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1998/001187 WO1998056950A1 (fr) | 1997-06-11 | 1998-06-10 | Sequences d'adn riches en triplet repete utiles dans le diagnostic de maladies a repetition trinucleotidique |
Country Status (3)
Country | Link |
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EP (1) | EP0988399A1 (fr) |
FR (1) | FR2764611B1 (fr) |
WO (1) | WO1998056950A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003014396A1 (fr) * | 2001-08-06 | 2003-02-20 | Biomedlab Corporation | Procede de diagnostic destine a une maladie de multiplication de sequence repetee de trinucleotides, et kit de diagnostic |
WO2012030224A1 (fr) | 2010-09-02 | 2012-03-08 | Holland Colours N.V. | Additif de matage et/ou de givrage pour des polymères ou des mélanges de polymères |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2252727A1 (fr) * | 1998-11-03 | 2000-05-03 | Ridha Joober | Polyglutamine contenant des proteines et son utilisation pour le diagnostic et le traitement de troubles neuropsychiatriques associes aux repetitions cag |
WO2001018544A1 (fr) * | 1999-09-09 | 2001-03-15 | Mcgill University | Diagnostic, pronostic et traitement de maladies liees a la repetition trinucleotidique et de maladies liees aux inclusions intranucleaires |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992020825A1 (fr) * | 1991-05-24 | 1992-11-26 | Baylor College Of Medicine | Diagnostic du syndrome du chromosome x fragile |
WO1993017104A1 (fr) * | 1992-02-20 | 1993-09-02 | Massachusetts Institute Of Technology | Sequence adn du gene de dystrophie myotonique et ses utilisations |
WO1994028172A1 (fr) * | 1993-05-28 | 1994-12-08 | Medical Research Council | Sondes de detection du syndrome du chromosome x fragile |
WO1995001437A2 (fr) * | 1993-06-29 | 1995-01-12 | Regents Of The University Of Minnesota | Sequence de genes de l'ataxie spino-cerebelleuse du type 1 et procede de diagnostic |
WO1995025179A1 (fr) * | 1994-03-17 | 1995-09-21 | University Of Massachusetts Medical Center | DETECTION DES REPETITIONS TRINUCLEOTIDIQUES PAR HYBRIDATION $i(IN SITU) |
WO1997030178A2 (fr) * | 1996-02-15 | 1997-08-21 | Fondation Jean Dausset-Ceph | Diagnostic des maladies a repetition trinucleotidique et genes impliques dans ces maladies |
WO1997042314A1 (fr) * | 1996-05-08 | 1997-11-13 | Cedars-Sinai Medical Center | Acide nucleique codant pour l'heredo-ataxie cerebelleuse du type 2 et produits connexes |
-
1997
- 1997-06-11 FR FR9707225A patent/FR2764611B1/fr not_active Expired - Fee Related
-
1998
- 1998-06-10 WO PCT/FR1998/001187 patent/WO1998056950A1/fr not_active Application Discontinuation
- 1998-06-10 EP EP98929536A patent/EP0988399A1/fr not_active Withdrawn
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992020825A1 (fr) * | 1991-05-24 | 1992-11-26 | Baylor College Of Medicine | Diagnostic du syndrome du chromosome x fragile |
WO1993017104A1 (fr) * | 1992-02-20 | 1993-09-02 | Massachusetts Institute Of Technology | Sequence adn du gene de dystrophie myotonique et ses utilisations |
WO1994028172A1 (fr) * | 1993-05-28 | 1994-12-08 | Medical Research Council | Sondes de detection du syndrome du chromosome x fragile |
WO1995001437A2 (fr) * | 1993-06-29 | 1995-01-12 | Regents Of The University Of Minnesota | Sequence de genes de l'ataxie spino-cerebelleuse du type 1 et procede de diagnostic |
WO1995025179A1 (fr) * | 1994-03-17 | 1995-09-21 | University Of Massachusetts Medical Center | DETECTION DES REPETITIONS TRINUCLEOTIDIQUES PAR HYBRIDATION $i(IN SITU) |
WO1997030178A2 (fr) * | 1996-02-15 | 1997-08-21 | Fondation Jean Dausset-Ceph | Diagnostic des maladies a repetition trinucleotidique et genes impliques dans ces maladies |
WO1997042314A1 (fr) * | 1996-05-08 | 1997-11-13 | Cedars-Sinai Medical Center | Acide nucleique codant pour l'heredo-ataxie cerebelleuse du type 2 et produits connexes |
Non-Patent Citations (5)
Title |
---|
LI S -H ET AL: "NOVEL TRIPLET REPEAT CONTAINING GENES IN HUMAN BRAIN: CLONING, EXPRESSION, AND LENGTH POLYMORPHISMS", GENOMICS, vol. 16, no. 3, June 1993 (1993-06-01), pages 572 - 579, XP000196589 * |
NÉRI C. ET AL.,: "Survey of CAG/CTG repeats in human cDNAs representing new genes: candidates for inherited neurological disorders", HUMAN MOLECULAR GENETICS, vol. 5, no. 7, - 1996, pages 1001 - 1009, XP002078949 * |
PUJANA M. A. ET AL.,: "Cloning (CAG/GTC)n STSs by an ALu-(CAG/GTC)n PCR method: an approach to human chromosome 12 and spinocerebellar ataxia 2 (SCA2)", NUCLEIC ACIDS RESEARCH, vol. 24, no. 18, - 1996, pages 3651 - 3652, XP002059375 * |
TAKEUCHI T. ET AL.,: "Molecular cloning and expression of a novel human cDNA containing CAG repeats", GENE, vol. 204, - 19 December 1997 (1997-12-19), pages 71 - 77, XP002059376 * |
YING-HUI FU ET AL: "VARIATION OF THE CGG REPEAT AT THE FRAGILE X SITE RESULTS IN GENETIC INSTABILITY: RESOLUTION OF THE SHERMAN PARADOX", CELL, vol. 67, no. 6, 20 December 1991 (1991-12-20), pages 1047 - 1058, XP000371773 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003014396A1 (fr) * | 2001-08-06 | 2003-02-20 | Biomedlab Corporation | Procede de diagnostic destine a une maladie de multiplication de sequence repetee de trinucleotides, et kit de diagnostic |
WO2012030224A1 (fr) | 2010-09-02 | 2012-03-08 | Holland Colours N.V. | Additif de matage et/ou de givrage pour des polymères ou des mélanges de polymères |
Also Published As
Publication number | Publication date |
---|---|
FR2764611A1 (fr) | 1998-12-18 |
FR2764611B1 (fr) | 2002-02-01 |
EP0988399A1 (fr) | 2000-03-29 |
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