EP1015574A1 - Polymorphic cag repeat-containing gene and uses thereof - Google Patents

Polymorphic cag repeat-containing gene and uses thereof

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Publication number
EP1015574A1
EP1015574A1 EP98943607A EP98943607A EP1015574A1 EP 1015574 A1 EP1015574 A1 EP 1015574A1 EP 98943607 A EP98943607 A EP 98943607A EP 98943607 A EP98943607 A EP 98943607A EP 1015574 A1 EP1015574 A1 EP 1015574A1
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EP
European Patent Office
Prior art keywords
gene
schizophrenia
patients
allelic variants
hgtl
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EP98943607A
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German (de)
English (en)
French (fr)
Inventor
Guy A. Rouleau
Ridha Joober
Chawki Benkelfat
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McGill University
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McGill University
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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
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • 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
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • 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
    • C12Q2600/118—Prognosis of disease development
    • 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 invention relates to hGTl gene, a polymorphic CAG repeat-containing gene and its uses thereof for the diagnosis, prognosis and treatment of psychiatric diseases, such as schizophrenia.
  • Schizophrenia is a chronic brain disorder characterized by a behavioral syndrome combining in various degrees hallucinations, delusions, social withdrawal, affective flattening, disorganized behavior and formal thought disorders. It affects up to 1% of the general population and results in a lower level of social and occupational functioning. Many recent studies indicate that schizophrenia may originate from neural cell disturbances occurring m the developing/maturing brain. Genetic factors are known to play a major role m the etiology of this disorder as demonstrated by extensive family, twin and adoption studies. However, the quest for genes conferring susceptibility to schizophrenia has been difficult and has not yielded consistent find- mgs using both association and linkage studies.
  • HVA High pre-treatment plasma levels of HVA have been shown to predict good response to neuroleptics m most of the studies.
  • Preliminary genetic epidemiological data indicate that poor or delayed response to neuroleptic treatment is associated with an increased prevalence of schizophrenia spectrum disorders m relatives of schizophrenic probands .
  • These convergent lines of evidence suggest that long term response to neuroleptic medication may be considered as a bioclinical dimension with an etio- logically relevant significance; the two extremes of this dimension being occupied by two groups of schizophrenic patients, at least partially, distinct with respect to the pathogeny of their illness.
  • One aim of the present invention is to provide a tool for the diagnosis, prognosis and treatment of psychiatric diseases, such as schizophrenia.
  • Another aim of the present invention is to detect association between allelic variants of CAG repeat -containing genes and schizophrenia or its pheno- typic variability with respect to long term response to neuroleptic medication.
  • CAG repeat instability was associated with several neurodegenerative brain diseases that display genetic anticipation, a feature believed to be present m schizophrenia
  • some ISO- lated, though promising, reports indicate that expanded CAG repeats are more prevalent m schizophrenic patients compared to normal controls
  • CAG repeats are often very polymorphic and have been found to be over represented m coding sequences of the human genome particularly those coding for DNA-bmdmg proteins/transcription factors.
  • CAG repeats or the polyglutamine stretches for which they encode
  • CAG repeats might modulate the function of the genes (or protein) they are pare of suggesting that they might be functional polymorphisms and not silent ones.
  • a hGTl gene containing transcribed polymorphic CAG repeat which comprises a sequence as set forth in Fig. 3 and Figs. 4A-4C.
  • allelic variants of CAG repeat of hGTl gene may be associated with schizophrenia, affective diseases such as manic depression, neurodevelopmental brain diseases or with phenotypic variability with respect to long term response to neuroleptic medication. More precisely, there are 5 allelic variants of
  • CAG repeat which are identified as follows:
  • a method for the prognosis of severity of schizophrenia of a patient which comprises the steps of: a) obtaining a nucleic acid sample of the patient; and b) determining allelic variants of CAG repeat of the hGTl gene, and wherein long allelic variants are indicative of severe schizophrenia.
  • the preferred nucleic acid sample used m accordance with the present invention is DNA.
  • RNA sample an additional step is carried out, which consists m using a reverse transc ⁇ ptase to transcribe the RNA into DNA.
  • allelic variants identified as short or as having between about 171 and 177 bp are associated with mild schizophrenia and long or as having between about 180 and 183 bp (referred to as 0 and 1) are associated with severe schizophrenia.
  • a method for the identification of patient responding to neuroleptic medication which comprises the steps of: a) obtaining a nucleic acid sample of the patient; and b) determining allelic variants of CAG repeat of the hGTl gene, and wherein short allelic vari- ants are indicative of neuroleptic response.
  • allelic variants identified as short or as having between about 171 and 177 bp are associated with patient capable of neuroleptic response and long or as having between about 180 and 183 bp (referred to as 0 and 1) are associated with non-response to neuroleptic medication.
  • a non-human mammal model for the hGTl gene whose germ cells and somatic cells are modified to express at least one allelic variant of the hGTl gene and wherein the allelic variant of the hGTl being introduced into the mammal, or an ancestor of the mammal, at an embryonic stage.
  • a method for the identification of patient responding to neuroleptic medication which comprises the steps of : a) obtaining a nucleic acid sample of the patient; and b) determining allelic variants of CAG repeat of the hGTl gene, and wherein short allelic variants (from about 171 to about 177 bp) are indicative of neuroleptic response.
  • a method for the screening of therapeutic agents for the prevention and/or treatment of schizophrenia which comprises the steps of: a) administering said therapeutic agents to the non-human mammal of the present invention or schizophrenia patients; and b) evaluating the prevention and/or treatment of development of schizophrenia m said mammal or said patients.
  • a method to identify genes part of or interacting with a biochemical pathway affected by hGTl gene which comprises the steps of: a) designing probes and/or primers using the hGTl gene of the present invention and screening psychiatric patients samples with said probes and/or primers; and b) evaluating the identified gene role m psychiatric patients.
  • a method of stratifying psychiatric patients based on the allelic variants of the hGTl gene for clinical trials purposes which comprises: a) obtaining a nucleic acid sample of the patients; and b) determining allelic variants of CAG repeat of the hGTl gene, wherein patients are stratified with respect to their allelic variants and wherein short allelic variants are indicative of neuroleptic response.
  • Fig. 1 illustrates the average allelic lengths of the GCT10D04 EST CAG repeat in controls, responsive (R) and non-responsive (NR) patients, showing the shorter (S) allele only, longer (L) allele only and the sum (L+S) of the two alleles m the three groups of subjects;
  • Fig. 2 illustrates the correlation between the average length of the (CAG)n polymer of the short (a) , the long (b) alleles and the sum of 2 alleles (C) and seventy of schizophrenia m the different classes of severity of the disease;
  • Fig. 3 illustrates the sequence homology between the human GCT10D04 sequence and the mouse GT1 gene; and
  • Figs. 4A-4C illustrate the nucleotide sequence of hGTl, wherein the upstream intron is m lowercase
  • Human gene sequence (exon) is m upper case; and the transcription start site ATG in bold.
  • the main objective was to detect allelic variants of CAG repeat containing genes associated with schizophrenia or its phenotypic variability with respect to the presence or absence of schizophrenia and long term response to neuroleptic medication.
  • Assessment of response to conventional neuroleptics was based on a comprehensive review of medical files according to a priori defined criteria and blind to genotyp g.
  • Genes containing polymorphic CAG repeats were identified by means of genetic sequences data base searches.
  • the GT1 sequence includes a 5535 bp open- reading frame (ORF) of 5535 bps without interruption showing 85%homology to the mouse cDNA (Figs. 4A-4C) .
  • the sequence of GT1 is from one large (5276 bp) Bam HI fragment and three Pst I fragments (672, 200 and 371 bps) .
  • This ORF is preceded by a 490 bps intron (including a consensus splice acceptor) and 19 bps of 5'-UTR.
  • the entire ORF may be coded for by a single exon (we are still missing the sequences coding for the last 12 amino acids (36 bp) .
  • NRs schizophrenic patients were recruited according to the following criteria: (1) they all met axis I diagnosis of schizophrenia, according to the Diagnostic and Statistical Manual of Mental Disorders, version IV (American Psychiatric association, Diagnos- tic and Statistical Manual of Mental Disorders, APA; 1994) (DSM-IV) , (2) they did not experience remission of psychotic symptoms within the past 2 years, (3) the preceding 5 years, all patients underwent at least 3 periods of treatment with typical neuroleptics, from at least two distinct families of drugs, at therapeutic dosage (equal to or greater than 750 mg Chlorpromazme equivalent in monotherapy or 1000 mg chlorpromazme equivalent, when a combination of neuroleptics is used) , for a continuous period of at least 6 weeks at a time, with no significant relief of symptoms, and; (4) Unable to function without supervision m all or nearly all domains of social and vocational activities with a Global Assessment Score (GAS) ⁇ 40 withm the last 12 months .
  • GAS Global Assessment Score
  • Criteria for the selection of neuroleptic Rs patients were as follows: (1) all patients met the criteria for schizophrenia according to DSM-IV, (2) all were admitted at least once to a psychiatric care facility because of acute psychotic episode, (3) during all hospitalizations, patients experienced full or partial remission response to treatment with typical neuroleptics, at recommended dosage, withm six-eight weeks of continuous treatment; remission being defined as a rapid reduction of schizophrenic symptoms with limited residual symptoms, (4) all patients were able to function with only occasional supervision in all or nearly all domains of social and vocational activities with a GAS score > 60 withm the last 12 months, (5) no patients had to be admitted to hospitals because of psychotic exacerbation, if and when compliant to treatment and treated continuously with typical neuroleptics, and; (6) at least one psychotic relapse when neuroleptic medication is reduced or interrupted. Exclu- sion criteria for schizophrenic patients were brain trauma, any neurological condition, drug or alcohol abuse in the last two years.
  • BLAST Basic Local Alignment Search Tool
  • PCR primers were designed using DNASTAR Inc. (Madison, Wisconsin) software .
  • Genom c DNA was isolated from peripheral lymphocytes using standard methods. CAG repeat -containing fragments were amplified by PCR using specific primers for each repeat . PCR was performed m a total volume of 13 ⁇ l containing 30 ng of human genomic DNA, lOmM Tris-HCl (pH 8.8), 1.5 mM MgCl 2 , 50mM KC1 , 1% Dimethyl- sulfoxide, 250 mM each of dCTP, dGTP, and dTTP, 25 mM dATP, 1.5 uCi alpha 35S-dATP, 100 ng of each primer, and 3 units of Taq polymerase (Perkm-Elmer) .
  • DNA was denatured at 94°C for 5 mm., then subjected to 30 cycles of a 1 mm. denaturation at 94°C, a 1 mm. annealing at the optimized annealing temperature for each primer pair and a 1 mm. elongation at 72°C. This was followed by a final extension at 72°C for 5 mm.
  • N LP response score 1 83 ⁇ 0 74 (58) " 6 3 ⁇ 0 67 (43)
  • Table 1 shows the demographic and clinical characteristics of the three groups of subjects Rs, NRs, and C.
  • Table 2 shows the sixteen different candidate expressed CAG repeats identified and analyzed and includes mapping, homology, and polymorphism information. Table 2: list of different studied ESTs
  • PCR indicates Polycham Reaction, RT-PCR, reverse rra ⁇ scnp ⁇ on PCR-reaction, PNQ, potenlial number of encoded polyglutanines, TF transcription factor; ER, estrogen receptor. RA. reuno c acid receptor
  • the reference point to measure the CAG repeat length is the most common allele (180 bp fragment or 14 predicted repeats), which is taken as 0. Alleles with n repeats above or below the 0 allele are scored +n or -n.
  • C indicates the control group; Rs, neuroleptic responsive schizophrenic patients group; and NRs, neuroleptic non-responsive schizophrenic patients group. A similar trend was observed for the S allele
  • At least one parent is non French Canadian
  • Allelic frequencies are given as percent of alleles shorter than 0 ( ⁇ 0) . Frequencies are analyzed according to different diagnosis groups and ethnic background of parents. All frequencies were contrasted with the frequencies of the alleles shorter than 0 in the control group.
  • SCZ indicates schizophrenic patients; Rs, neuroleptic-responsive schizophrenic patients; NRs, neuroleptic non-responsive schizophrenic patients, and; ⁇ 2 , Chi 2 statistic with 1 degree of freedom
  • the size of the CAG repeat tract is linearly related to the pattern of severity of schizophrenia (measured blindly to genotype, using a 1-5 scoring system defined as follows: (1, episodic shift) episodes of illness interspersed between periods of health or near normal - ity, (2, mild deterioration) periods of illness occur, but there are periods of return to near normality, with some ability to work at a job and near normal or normal social functioning, (3, moderate deterioration) , the subject may occasionally experience some resolution of symptoms, but overall the course is downhill culminating in a relatively sever degree of social and occupational incapacitation, (4, severe deterioration) , the subject illness has become chronic resulting in inability to maintain employment (outside of a sheltered workshop) and social impairment, and; (5, relatively stable) , the subject illness has not changed significantly (since it started at a severe level of impairment) ; the longer the size, the worse and poorer is the outcome (Gamma statistic for S, L and L+S allele
  • the GCT10D04 sequence was 84% homologous to a mouse gene (GTl, GenBank D29801, see figure 3) from which is transcribed a 7.2 kb cDNA encoding a 196 kDa protein of unknown function, suggesting that GCT10D04 represents a portion of the human homologue, which we term hGTl.
  • the murine GTl gene is inducible with retinoic acid in the mouse embryonic carcinoma cell line P19 and is expressed at highest levels in neurons but not in glial cells.
  • a sequence homology search using the GTl protein sequence identified several conserved domains in another mouse gene (stromelysin PDGF responsive element binding protein transcription factor, GenBank U20282) and in its human homologue (AR1, GenBank U19345) , suggesting that the hGTl protein may also function as a transcription factor.
  • Common allelic variants rather than rare mutations, may be responsible for the familial aggregation observed in complex diseases such as schizophrenia. Allelic variants that are neither necessary nor sufficient to cause a disease may not be identified by link- age analysis, particularly when the attributable risk is less than 10%. In contrast, association studies are sensitive to detect such variants.
  • neu- roleptic-responsive-schizophrenic patients were sig- nificantly more likely to have hGTl gene alleles with short CAG repeats as compared to patients who are characterize by long term poor response to neuroleptics and outcome. Furthermore, a significant correlation between the size of the hGTl CAG repeat and the pattern of severity of the disease (the longer is the CAG repeat the more severe is the outcome) was identified in the group of schizophrenic patients regardless of the quality of their response to neuroleptic medication.
  • association studies with a relatively small number of subjects and a potentially high number of genes to be tested is an increased risk of false positive findings (type I error) .
  • hGTl polymorphism modulates the pattern of severity of the schizophrenia phenotype but not the susceptibility to schizophrenia per se (modifier gene hypothesis)
  • hGTl gene could influence susceptibility to schizophrenia irrespective of the pattern of severity and responsiveness to neuroleptics; the weak associa- tion in the group of resistant schizophrenic patients being the result of a selection bias.
  • Transcription factors are major actors m all neurodevelopmental phases, and might be very important when developmental activity is intensive such as bram fetal development or synaptic pruning occurring m the adolescence phase of human development. They have been implicated m animal complex behavioral traits and have also a major role in the transduction pathways involved in the biological adaptation of the central nervous system to environmental changes (ranging from physical conditions such as viral infections to psychological conditions such as nurturing behavior m mice) . It is also of interest to note that all antipsychotic drugs modulate DNA transcription m specific areas of the bram and ultimately results m modifications of neu- ronal interconnec lvity.

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EP98943607A 1997-09-19 1998-09-18 Polymorphic cag repeat-containing gene and uses thereof Withdrawn EP1015574A1 (en)

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CA 2216057 CA2216057A1 (en) 1997-09-19 1997-09-19 Polymorphic cag repeat-containing gene, diagnosis of psychiatric diseases and therapeutic uses thereof
CA2216057 1997-09-19
PCT/CA1998/000884 WO1999015639A1 (en) 1997-09-19 1998-09-18 Polymorphic cag repeat-containing gene and uses thereof

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JP (1) JP2001517432A (ja)
AU (1) AU757556B2 (ja)
BR (1) BR9812254A (ja)
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WO (1) WO1999015639A1 (ja)

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DE19835910C1 (de) * 1998-08-07 2000-05-04 Deutsches Krebsforsch Gen isoliert auf dem kurzen Arm des menschlichen Chromosoms 17
JP2004522418A (ja) * 2000-09-08 2004-07-29 アイオワ ステート ユニバーシティ リサーチ ファウンデーション，インコーポレーティッド 新規なｐｒｋａｇ３対立遺伝子並びに生殖性及び肉質の形質の遺伝標識としてのその使用
GB0228079D0 (en) * 2002-12-02 2003-01-08 Laxdale Ltd Huntington's Disease
WO2008032056A2 (en) * 2006-09-16 2008-03-20 Genophrenix Limited Dopamine receptor interacting proteins as markers for disease

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US5834183A (en) * 1993-06-29 1998-11-10 Regents Of The University Of Minnesota Gene sequence for spinocerebellar ataxia type 1 and method for diagnosis
CA2238075A1 (en) * 1995-11-17 1997-05-29 The University Of British Columbia Protein which interacts with the huntington's disease gene product, cdna coding therefor, and antibodies thereto

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