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WO2001009161A1 - Isogenes cibles de medicaments: polymorphismes dans le gene membre 4 de la famille 6 des transporteurs-solutes, transporteur du neurotransmetteur serotonine - Google Patents

Isogenes cibles de medicaments: polymorphismes dans le gene membre 4 de la famille 6 des transporteurs-solutes, transporteur du neurotransmetteur serotonine Download PDF

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Publication number
WO2001009161A1
WO2001009161A1 PCT/US2000/020638 US0020638W WO0109161A1 WO 2001009161 A1 WO2001009161 A1 WO 2001009161A1 US 0020638 W US0020638 W US 0020638W WO 0109161 A1 WO0109161 A1 WO 0109161A1
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WO
WIPO (PCT)
Prior art keywords
seq
slc6a4
gene
adenine
thymine
Prior art date
Application number
PCT/US2000/020638
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English (en)
Inventor
R. Rex Denton
Amy Duda
Krishnan Nandabalan
Angela Sanchis
Joel Claiborne Stephens
Original Assignee
Genaissance Pharmaceuticals, Inc.
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 Genaissance Pharmaceuticals, Inc. filed Critical Genaissance Pharmaceuticals, Inc.
Priority to AU66127/00A priority Critical patent/AU6612700A/en
Publication of WO2001009161A1 publication Critical patent/WO2001009161A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • 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
    • 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
    • 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
    • C12Q2535/00—Reactions characterised by the assay type for determining the identity of a nucleotide base or a sequence of oligonucleotides
    • C12Q2535/125—Allele specific primer extension
    • 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
    • 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
    • C12Q2600/172—Haplotypes

Definitions

  • Solute carrier family 6 _neurotransmitter transporter serotonin_, member 4 (SLC6A4) gene or its encoded product.
  • the solute carrier family 6, member 4 (SLC6A4) gene also known as human serotonin transporter (HSERT) and 5- hydroxytryptamine transporter (5-HTT), is the primary target of many antianxiety and antidepressant drugs, including citalopram, fluoxetine and other selective serotonin reuptake inhibitors, as well as tricyclic compounds such as impramine (Ramamoorthy et al., Proc. Natl. Acad.
  • the polymorphisms at these sites are thymine or cytosine at PSI, thymine or adenine at PS2, thymine or cytosine at PS3, thymine or cytosine at PS4, cytosine or thymine at PS5, guanine or cytosine at PS6, adenine or cytosine at PS7, adenine or cytosine at PS8, guanine or adenine at PS9, cytosine or adenine at PSI 1, guanine or adenine at PS 12, guanine or thymine at PS 13, guanine or cytosine at PS14, thymine or cytosine at PS15, guanine or adenine at PS16, cytosine or thymine at PS17, cytosine or thymine at PS 18, guanine or adenine at PS 19, adenine or guanine at PS20, adenine or gu
  • the methods and compositions for establishing the genotype or haplotype of an individual at the novel polymo ⁇ hic sites described herein are useful for studying the effect of the polymo ⁇ hisms in the etiology of diseases affected by the expression and function of the SLC6A4 protein, studying the efficacy of drugs targeting SLC6A4, predicting individual susceptibility to diseases affected by the expression and function of the SLC6A4 protein and predicting individual responsiveness to drugs targeting SLC6A4.
  • the invention provides a method for identifying an association between a genotype or haplotype and a trait.
  • the trait is susceptibility to a disease, severity of a disease, the staging of a disease or response to a drug.
  • FIG. 9 illustrates a partial reference sequence for the SLC6A4 gene (Genbank Version Number
  • Haplotype pair The two haplotypes found for a locus in a single individual.
  • Haplotyping A process for determining one or more haplotypes in an individual and includes use of family pedigrees, molecular techniques and/or statistical inference.
  • Haplotype data Information concerning one or more of the following for a specific gene: a listing of the haplotype pairs in each individual in a population; a listing of the different haplotypes in a population; frequency of each haplotype in that or other populations, and any known associations between one or more haplotypes and a trait.
  • polymo ⁇ hic variants of the SLC6A4 gene will produce SLC6A4 mRNAs varying from each other at any polymo ⁇ hic site retained in the spliced and processed mRNA molecules.
  • These mRNAs can be used for the preparation of a SLC6A4 cDNA comprising a nucleotide sequence which is a polymo ⁇ hic variant of the SLC6A4 reference coding sequence shown in Figure 11.
  • the invention also provides SLC6A4 mRNAs and corresponding cDNAs which comprise a nucleotide sequence that is identical to SEQ ID NO:l 1 (Fig.
  • Transgenic animals stably expressing a human SLC6A4 isogene and producing human SLC6A4 protein can be used as biological models for studying diseases related to abnormal SLC6A4 expression and/or activity, and for screening and assaying various candidate drugs, compounds, and treatment regimens to reduce the symptoms or effects of these diseases.
  • an individual's SLC6A4 haplotype pair is predicted from its SLC6A4 genotype using information on haplotype pairs known to exist in a reference population.
  • the haplotyping prediction method comprises identifying a SLC6A4 genotype for the individual at two or more polymo ⁇ hic sites selected from PSI, PS2, PS3, PS4, PS5, PS6, PS7, PS8, PS9, PS11, PS12, PS13, PS14, PS15, PS16, PS17, PS18, PS19, PS20, PS21, PS22, PS23, PS24, PS25, PS26, PS28, PS29, PS30, PS31, PS32, and PS33, enumerating all possible haplotype pairs which are consistent with the genotype, accessing data containing SLC6A4 haplotype pairs identified in a reference population, and assigning a haplotype pair to the individual that is consistent with the data.
  • Sequencing reactions were performed using the Big-Dye terminator kit from PE Biosystems (Foster City, CA) according to the manufacturer's instructions. The sequencing products were analyzed on an ABI 477 automated sequencer (PE Biosystems, Foster City, CA).

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Physics & Mathematics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Pathology (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicinal Chemistry (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention concerne des polynucléotides comprenant un ou plusieurs polymorphismes parmi 31 nouveaux polymorphismes de nucléotides en un seul site, dans le gène membre 4 de la famille 6 des transporteurs-solutés, transporteur du neurotransmetteur sérotonine (SLC6A4). Elle porte également sur des compositions et des procédés de détection d'un ou plusieurs de ces polymorphismes. Par ailleurs, divers génotypes et haplotypes pour le gène SLC6A4 existant dans la population sont décrits.
PCT/US2000/020638 1999-07-29 2000-07-31 Isogenes cibles de medicaments: polymorphismes dans le gene membre 4 de la famille 6 des transporteurs-solutes, transporteur du neurotransmetteur serotonine WO2001009161A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU66127/00A AU6612700A (en) 1999-07-29 2000-07-31 Drug target isogenes: polymorphisms in the solute carrier family 6 neurotransmitter transporter, serotonin , member gene

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14629099P 1999-07-29 1999-07-29
US60/146,290 1999-07-29

Publications (1)

Publication Number Publication Date
WO2001009161A1 true WO2001009161A1 (fr) 2001-02-08

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PCT/US2000/020638 WO2001009161A1 (fr) 1999-07-29 2000-07-31 Isogenes cibles de medicaments: polymorphismes dans le gene membre 4 de la famille 6 des transporteurs-solutes, transporteur du neurotransmetteur serotonine

Country Status (2)

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AU (1) AU6612700A (fr)
WO (1) WO2001009161A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003029410A3 (fr) * 2001-09-28 2003-10-23 Millenium Pharmaceuticals Inc Methodes d'utilisation de 69039, nouveau membre de la famille des echangeurs na/ca humains
US8355927B2 (en) 2010-11-05 2013-01-15 Genomind, Llc Neuropsychiatric test reports

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LESCH K.P. ET AL.: "Organization of the human serotonin transporter gene", JOURNAL OF NEURAL TRANSMISSION GENERAL SECTION, vol. 95, 1994, pages 157 - 162, XP002933893 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003029410A3 (fr) * 2001-09-28 2003-10-23 Millenium Pharmaceuticals Inc Methodes d'utilisation de 69039, nouveau membre de la famille des echangeurs na/ca humains
US7045505B2 (en) 2001-09-28 2006-05-16 Millennium Pharmaceuticals, Inc. Methods of using 69039, a novel human Na/Ca exchanger family member
US8355927B2 (en) 2010-11-05 2013-01-15 Genomind, Llc Neuropsychiatric test reports
US8706526B2 (en) 2010-11-05 2014-04-22 Genomind, Llc Neuropsychiatric test reports

Also Published As

Publication number Publication date
AU6612700A (en) 2001-02-19

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