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WO2003033737A1 - Procede de detection de genes au moyen d'adn mitochondrial humain - Google Patents

Procede de detection de genes au moyen d'adn mitochondrial humain Download PDF

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Publication number
WO2003033737A1
WO2003033737A1 PCT/JP2002/010640 JP0210640W WO03033737A1 WO 2003033737 A1 WO2003033737 A1 WO 2003033737A1 JP 0210640 W JP0210640 W JP 0210640W WO 03033737 A1 WO03033737 A1 WO 03033737A1
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Prior art keywords
amino acid
group
acid substitutions
dna
mitochondrial dna
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PCT/JP2002/010640
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English (en)
Japanese (ja)
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Masashi Tanaka
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Gifu International Institute Of Biotechnology
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Publication of WO2003033737A1 publication Critical patent/WO2003033737A1/fr

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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
    • 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 a method for detecting human mitochondrial DNA genes.
  • Mitochondria are subcellular organelles found in eukaryotic cells that use the oxidative phosphorylation system within them to supply most of the energy needed for cell activity. In this mitochondria, it was revealed that there was a mitochondrial DNA independent of nuclear DNA (hereinafter abbreviated as “mt DNAj”).
  • mt DNAj mitochondrial DNA independent of nuclear DNA
  • the present inventor thought that there might be a correlation between mt DNA mutations and adult diseases, and as a result of intensive studies, found that there was a certain correlation between specific mutations and adult diseases.
  • the invention disclosed in Japanese Unexamined Patent Application Publication No. 11-11397 was made.
  • “Medium,” Confucius (55 1-47, 79 BC) argues that "Medium of Kimiko, anti-medium of dwarfs.”
  • Aristotle (384-32-22 BC) also discusses such a concept of mediumness in Nicomachus ethics.
  • the present invention has been made in view of the above circumstances, and an object of the present invention is to provide a gene detection method for confirming amino acid substitution in mtDNA. Disclosure of the invention
  • the inventor of the present invention has stated that, among centenarians (those who have a life expectancy of 99.1 years or older at full age), mitochondrial mutations are low, that is, centuries have genetically moderate. In order to test this hypothesis and to test this hypothesis, 64 people from 100 years old, 96 patients with Parkinson's disease, and 6 young adults (from 20 to 30 years old) 9 The following facts were clarified by determining the nucleotide sequence of the cytochrome b (cytochrome b) gene in mt DNA for each group of 6 people, comparing and examining the position and frequency of amino acid substitutions between each group. Basically, the present invention has been completed.
  • two amino acids sandwiching a number mean one amino acid substitution.
  • the first letter indicates the amino acid before substitution
  • the second letter indicates the amino acid after substitution.
  • the numbers indicate the positions at which the amino acid substitutions were made in the amino acid sequence of cytochrome b.
  • I306V means that the mutation is obtained by replacing isoleucine at position 306 with valine.
  • N260D was found at a frequency of 6.25% (4/64) in the 100-year-old group, whereas it was 1 in both the young adult group (1/96) and the Parkinson's disease group (1/96). . Found at a frequency of 04%.
  • the frequency of G251S replacement in other disease control groups was intermediate between that in the Parkinson's disease group (6.9%) and that in the centenarian group (0.0%).
  • the first invention for achieving the above object is a method for detecting a gene using human mitochondrial DNA, wherein the base sequence of the human mitochondrial DNA is encoded by its base sequence. It is characterized by detecting that a protein has been substituted with a base accompanied by amino acid substitution.
  • the “base sequence” often determines the base sequence of mt DNA as it is, but becomes ⁇ type by determining the base sequence of complementary DNA or mRNA. It is also possible to determine the base sequence of mt DNA. It is also known to those skilled in the art that the genetic code of mt DNA includes non-universal codes (for example, UGA, a common stop codon, encodes tryptophan, and AUA (often encodes isoloisin). Note that) encodes Mechiyun.)
  • base substitution means that a specific base is substituted as compared with the so-called “revised Cambridge standard sequence”.
  • base substitution does not necessarily involve amino acid substitution.
  • triplets three consecutive base sequences
  • stop codon the triplet after substitution will be This is because it may encode the same amino acid as before.
  • amino acids are represented by one-letter codes in principle.
  • the base sequence encodes cytochrome b (SEQ ID NO: 1), wherein the amino acid substitution is T2A, T2I, H16R, A39T, T47K, T61A, I78T, L82F.
  • the base sequence encodes cytochrome b (SEQ ID NO: 1), wherein the amino acid substitution is T2A, T2I, T47K, T61A, L82F, Y109H, T158A, D159N. , D171N, A190T, A193T, F245L, P247A, G251S, L296M, I300T, I338V, S344N, A354T, I372V, and A380T.
  • the amino acid substitutions described here exclude all 9 amino acid substitutions found in the 100-year-old group.
  • the nucleotide sequence encodes cytochrome b (SEQ ID NO: 1), wherein the amino acid substitution is T2I, T47K, T61A, ⁇ , D171N, A190T, F245L, P247A. , I300T, S344N, and A354T.
  • the amino acid substitutions described here are amino acid substitutions specifically found only in the Parkinson's disease patient group.
  • the base sequence encodes cytochrome b (SEQ ID NO: 1), and the amino acid substitution is at least one of A193T, G251S, and I372V. It is characterized by being.
  • the amino acid substitutions described here are characteristic of the amino acid substitutions commonly found in the young adult group and the Parkinson's disease patient group.
  • FIG. 1 is a genetic map of mtDNA.
  • FIG. 2 is a conceptual diagram showing a sequence method of mtDNA.
  • FIG. 3 is a diagram showing a molecular phylogenetic network of amino acid substitutions of cytochrome b in centenarians, young adults, and patients with Parkinson's disease.
  • the lightly shaded circles in the figure indicate the number of individuals having a standard amino acid sequence or a common amino acid substitution. Open circles indicate amino acid substitutions found in centenarians, and filled circles indicate amino acid substitutions detected in Parkinson's disease patients or young adults.
  • FIG. 4 is a diagram showing a molecular phylogenetic network of amino acid substitutions of cytochrome b in centenarians, young adults, and patients with Parkinson's disease. Compared to FIG. 3, those having the same amino acid substitution in the three groups are shown as parameters (thin circles). Others are the same as in FIG. BEST MODE FOR CARRYING OUT THE INVENTION
  • the determination of the base system IJ of NA is performed, for example, by Masashi Tanaka, Mika Hayakawa, and Takayuki Ozawa, Automated Sequencing of Mitochondrial DNA, Methods in Enzymology,
  • GCCCGTCTAAACATTTTCAG is used to amplify about 300 bp of DNA.
  • This first PCR product contains the cytochrome b gene.
  • FL 2 FL 1 4 5 5 9 (SEQ ID NO: 5: GTAAAACGACGGCCAGTCGACCACACCGCTAACAATC), FL 1 4 8 3 7 (SEQ ID NO: 6: GTAAAACGACGGCCAGTTGAAACTTCGGCTCACTCCT), FL 1 5 1 2 6 (SEQ ID NO: 7: GTAAAACGACGGCCAGTCCTTCATAGGCTATGTCCTC), FL 1 5 4 0 5 (SEQ ID NO: 8 GTAAAACGACGGCCAGTTCCACCCTTACTACACAATC), FL 1 5 6 9 6 (SEQ ID NO: 9 GTAAAACGACGGCCAGTTTCGCCCACTAAGCCAATCA), FL 1 5 0 8 GTAAAACGACGGCCAGTAGGACAAATCAGAGAAAAAG)) and H2 (H15162 (SEQ ID NO: 11: TACTGTGGCCCCTCAGAATG)), H15340 (SEQ ID NO: 12: ATCCCGTTTCGTGCAAGAAT
  • the obtained base sequence is compared and analyzed by, for example, a computer.
  • multiple base substitutions are found in the mtDNA sequences of centenarians, young adults, and patients with Parkinson's disease.
  • not all of these base substitutions are accompanied by amino acid substitutions.
  • only base substitutions involving amino acid substitutions will be extracted and summarized for each group of centenarians, young adults, and Parkinson's disease patients. Further, sites where amino acid substitution in each group occurs particularly remarkably are specified.
  • a known method such as the Southern plot method, FISH method, RIGS method, CGH method, LOH method, direct sequence method, PCR-SSCP Gene detection can be performed by using the MASA method, MASA method, ASO probe method, PCR method, OPA method, etc. (BIOCLinica 10 (9), 1995, 18-23).
  • Example 2 Confirmation of the nucleotide sequence of the gene encoding cytochrome b in mtDNA of centenarians, young adults and patients with Parkinson's disease
  • the nucleotide sequence of the gene encoding cytochrome b was confirmed in the mtDNA of centenarians (64), young adults (96), and patients with Parkinson's disease (96). For those who live in Tokyo, Aichi and Gifu, blood cells or mucosal cells are collected from the people who have given their consent, and the total DNA is extracted. The sequence was confirmed. The DNA sequence was performed as follows based on the method reported in the above-mentioned Methods in Enzymology, Volume 264, 407-421, 1996. Table 1 shows the combinations of the primers DNA used in the first and second PCR methods.
  • the composition of the reaction solution is as follows. 1 1 total DNA (lOng /, 1), 51 L1 (10 / ⁇ ), 51 H1 (10 / zM), 41 2.5 mM dNTPs, 0.25 x 1 5 units // ⁇ 1 Taq DNA polymerase, 5 / z 1 10x PCR buffer (100 mM Tris-HC1, pH 8.3, 500 mM KC1, 15 raM MgCl 2 ), add 29.75 / il purified water to make a total volume of 50 ⁇ . Mix in a 0.2-ml MicroAmp tube.
  • This reaction solution was subjected to a PCR method using GeneAmp PCR system Model 9600 manufactured by PerkinElmer Inc.
  • the reaction conditions were: denaturation at 94 ° C for 15 seconds, annealing at 60 ° C for 15 seconds, 72.
  • the cycle of elongation for 185 seconds at C was defined as one cycle, and 40 cycles were repeated.
  • the first PCR product was used as a template, and FL 2 and H 2 were used as primers.
  • the composition of the reaction solution is as follows. 1 ⁇ l of the first PCR product solution, 2 ⁇ l of FL2 (10 ⁇ ), 2 ⁇ l of ⁇ 2 (10 ⁇ ) ⁇ 1.6 1 of 2.5 mM dNTP, 0.1 ⁇ 1 of 5 units / ⁇ 1 rTaq DNA
  • the polymerase and 2 ⁇ l of 10 ⁇ PCR buffer were mixed with 11.3 / zl of purified water to make a total volume of 20/1 in a 0.2-ml MicroAtnp tube.
  • the reaction conditions of the PCR method were as follows: thermal denaturation (94 ° C-15 seconds), annealing ( 60 ° C-I 5 seconds), extension reaction (72 ° C-3 minutes), and 40 cycles. .
  • the final extension reaction was performed at 72 ° C for 10 minutes.
  • 1.5 / X 1 of 3 M sodium acetate (pH 7.4) and 30 / xl of ethanol was added to the reaction solution, the mixture was allowed to stand on ice for 10 minutes, and centrifuged at 13,000 xg for 10 minutes at 4 ° C.
  • the precipitate was washed with 451 70% ethanol and centrifuged at 13,000 xg for 5 minutes at 4 ° C. After the precipitate was dried for 10 minutes, it was dissolved in 10 / il of purified water.
  • the sequence reaction was performed as follows.
  • the primer and dNTP were removed by an ultrafiltration method using PCR Screen (for Millipore 96iell). 280 ⁇ l of sterile water was added to the second PCR product (20 ⁇ ) to make 300 ⁇ L, and the mixture was dispensed into MultiScreen_PCR Plate. PCR plate to multi-stareenba The sample was attached to a vacuum manifold, aspirated at 24 inches Hg for 10 minutes, and subjected to ultrafiltration. 100 L of sterile water was dispensed into a PCR plate, shaken vigorously with a mixer for 5 minutes, and then transferred to a new PCR tube.
  • a premix optical terminator (DNA Sequencing Kit, BigDye TM Terminator Cycle Sequencing Ready Reaction, ABI PRISM, PE Applied Biosystems, Japan) was used.
  • a second time of the PCR product 2 mu 1 after ultrafiltration 2 / zl of Pretnix ⁇ ⁇ , - 21M13 Forward Primer (0.8 pmol / ⁇ 1) 4 z 1, 5 X Sequence Buff er 2 1, sterile water 8 mu ⁇ was added to bring the total volume to 20 l.
  • After the first heat denaturation (96 ° C-10 minutes), one cycle of heat denaturation (96 ° C-10 seconds), annealing (50 ° C-5 seconds), and extension reaction (60 ° C-4 minutes) This was repeated 25 cycles.
  • TSR Template Suppression Reagent
  • Example 3 Analysis of amino acid substitution in each group of centenarians, young adults, and Parkinson's disease patients
  • the gene encoding cytochrome b in mt DNA was obtained by the method described in Example 2. After determining the nucleotide sequence of the offspring, the nucleotide substitution and amino acid substitution were analyzed. Tables 2 and 3 show the presence or absence of the confirmed base substitution and amino acid sequence substitution. The meaning of the table is as follows. For example, the substitution on the first line in Table 2 shows that the adenylate (A) at position 14750 of mitochondrial DNA is replaced with guanine (G), and that the base substitution is made with the threonine of the second amino acid of cytochrome b. It means that it is an amino acid substitution to be replaced with an araen (ie, “T 2 A” described above).
  • FIGS. 3 and 4 visually show the amino acid substitutions in each group.
  • Fig. 3 shows the amino acid substitutions confirmed in each of all groups
  • Fig. 4 shows the amino acid substitutions confirmed in all three groups in the population. ing. Therefore, it is convenient to refer to Fig. 4 to confirm the amino acid substitution characteristic of each group.
  • 58 Mann-Whitney's U test
  • N260D was found at a frequency of 6.25% (4/64) in the 100-year-old group, whereas it was found in both the young adult group (1/96) and the Parkinson's disease group (1/96). Found at a frequency of 04%.
  • Deviations from the standard amino acid sequence are associated with increased production of reactive oxygen species from mitochondria, which can lead to age-related diseases.
  • the amino acid residue Gly251 is highly conserved in mammalian species. Gly251 is located at the outer binding site (Qo site) of ubiquinone in cytochrome b protein, and is located near Glu271 residue, which plays an important role in binding to ubiquinone. When Gly251 is replaced by Ser, Ser may form a hydrogen bond with Glu271. If this restricts the movement of Glu271, it is assumed that the binding of ubiquinone to the Qo site will change.
  • genotype Mt5178A is found at high frequency in Japanese centenarians (Tanaka M, Gong JS, Zhang J, Yoneda M, Yagi K. Mitochondrial genotype assoc iated with longevity Lancet 1998; 351: 185-6.) 0
  • Ivanova et al. Ivanova R, Lepage V, Charron D, Schachter F. Mitochondrial genotype associated with French Caucasian centenarians. Gerontology 1998; 44: 349.

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Abstract

L'invention vise à mettre en oeuvre un procédé de détection de gènes consistant à détecter une substitution d'acides aminés dans l'ADNmt, ladite substitution se révélant avantageuse ou non pour l'augmentation de la durée de vie chez les humains. L'invention concerne un procédé de détection de gènes faisant intervenir de l'ADN mitochondrial, consistant à coder le cytochrome b dans une séquence de bases d'ADN mitochondrial, et à détecter la substitution d'une base avec au moins un acide aminé choisi parmi T2A, T2I, H16R, A39T, T47K, T61A, I78T, L82F, Y109H, T158A, D159N, I164V, D171N, A190T, A191T, A193T, F245L, P247A, G251S, N260D, L296M, I300T, I306V, I338V, V343M, S344N, A354T, I369V, I372V ET A380T.
PCT/JP2002/010640 2001-10-17 2002-10-15 Procede de detection de genes au moyen d'adn mitochondrial humain WO2003033737A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995026973A1 (fr) * 1994-03-30 1995-10-12 Mitokor Diagnostic, therapie et modeles cellulaires et animaux concernant les affections associees aux anomalies mitochondriales
WO2000011219A1 (fr) * 1998-08-20 2000-03-02 The Johns Hopkins University School Of Medicine Mutations mitochondriales legerement perceptibles comme marqueurs de tumeurs
JP2000175689A (ja) * 1998-12-17 2000-06-27 Otsuka Pharmaceut Co Ltd ヒトミトコンドリアｄｎａ異常の検出方法
WO2001068923A2 (fr) * 2000-03-15 2001-09-20 The Johns Hopkins University Dosimetre a mitochondries

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995026973A1 (fr) * 1994-03-30 1995-10-12 Mitokor Diagnostic, therapie et modeles cellulaires et animaux concernant les affections associees aux anomalies mitochondriales
WO2000011219A1 (fr) * 1998-08-20 2000-03-02 The Johns Hopkins University School Of Medicine Mutations mitochondriales legerement perceptibles comme marqueurs de tumeurs
JP2000175689A (ja) * 1998-12-17 2000-06-27 Otsuka Pharmaceut Co Ltd ヒトミトコンドリアｄｎａ異常の検出方法
WO2001068923A2 (fr) * 2000-03-15 2001-09-20 The Johns Hopkins University Dosimetre a mitochondries

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANDREU A.L. ET AL.: "Missense mutation in the mtDNA cytochrome B gene in a patient with myopathy", J. CLIN. BIOCHEM. NUTR., vol. 28, 2000, pages 191 - 199, XP002962353 *
BROWN MICHAEL D. ET AL.: "Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy", GENETICS, vol. 130, no. 1, 1992, pages 163 - 173, XP002962352 *
MASASHI TANAKA ET AL.: "Common, rare and individual variations of mitochondrial DNA associated with disease or longevity", J. CLIN. BIOCHEM. NUTR., vol. 28, 2000, pages 191 - 199, XP002962351 *

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