CN1330774C - Kynurenine hydrolase polymorphism and its diagnostic use - Google Patents
Kynurenine hydrolase polymorphism and its diagnostic use Download PDFInfo
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- CN1330774C CN1330774C CNB021109249A CN02110924A CN1330774C CN 1330774 C CN1330774 C CN 1330774C CN B021109249 A CNB021109249 A CN B021109249A CN 02110924 A CN02110924 A CN 02110924A CN 1330774 C CN1330774 C CN 1330774C
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Abstract
The present invention relates to a single nucleotide polymorphism (SNP) of kynurenine hydrolase and a correlation of the kynurenine hydrolase with hypertension. The present invention provides a method for analyzing the SNP or the activity of kynurenine hydrolase genes and an application thereof to hypertension diagnosis. The SNP of the present invention is the G+[->]A polymorphism at the 57th bit in the kynurenine hydrolase genes in the genome or the G+[->]A polymorphism of the 669th bit in the kynurenine hydrolase genes with a sequence shown by SEQ ID NO. 1. The SNP leads to the R188Q change of encoding protein, so the enzyme activity is changed.
Description
Technical field
The present invention relates to the single nucleotide polymorphism of kynurenine hydrolase gene.The invention still further relates to the method for the allelic mutation of analyzing the kynurenine hydrolase gene, and the purposes of kynurenine hydrolase gene mononucleotide polymorphism aspect the diagnosis essential hypertension.
Background technology
KYNU (kynurenine hydrolase) be a kind of 5 ' pyridoxal phosphate (pyrdoxal-5 '-phosphate, PLP) dependent enzyme, catalysis L-kynurenine and L-3-hydroxykynurenine are cracked into anthracene aniline (anthranilic) and 3-hydroxyl anthracene aniline.It also participates in biological process (the Alberati-Giani D that tyrosine changes the NAD cofactor into by the kynuric acid path, Buchli R, Malherbe P, Isolation and expression of a cDNA cloneencoding human kynureninase.Eur J Biochem, 1996; 239 (2): 460-8).
Kynurenine is N-methyl D-Aspartic Acid (NMDA) receptor-blocking agent.The latter is a kind of central blood pressure regulation factor, has experiment to show that the quiet NMDA of pushing away can boost.
Before the application, also there is not the especially report of the dependency of essential hypertension of kynurenine hydrolase gene and disease, there is not the especially report of the dependency of essential hypertension of kynurenine hydrolase gene pleiomorphism and disease yet.
Summary of the invention
Purpose of the present invention just provides and kynurenine hydrolase gene and polymorphism and hypertensive dependency, and the purposes aspect the detection essential hypertension.
In a first aspect of the present invention, a kind of method of single nucleotide polymorphism of the people's of detection kynurenine hydrolase gene is provided, it comprises step:
(a) determine the 669th Nucleotide in sequence shown in the SEQ ID of the people's kynurenine hydrolase gene NO:1;
(b) detect whether there is single nucleotide polymorphism in described position.
In a preference, described single nucleotide polymorphism is to have A at the 669th.
In a second aspect of the present invention, a kind of isolating nucleic acid is provided, it has the sequence shown in the SEQ ID NO:1, and the 669th is A.
In a third aspect of the present invention, a kind of allele specific nucleic acid primer is provided, its length is 15-50bp, and hybridizes specifically and amplify shown in the SEQ ID NO:1 that contains people's kynurenine hydrolase gene the amplified production of the 669th single nucleotide polymorphism in the sequence.
In a fourth aspect of the present invention, a kind of allele specific oligonucleotide probe is provided, its length is 15-50bp, and hybridizes specifically and detect shown in the SEQ ID NO:1 that contains people's kynurenine hydrolase gene the 669th single nucleotide polymorphism in the sequence.
In fifth aspect present invention, provide and detected hypertensive diagnostic kit.
A kind of test kit comprises:
(1) primer of specific amplification people kynurenine hydrolase gene is right,
(2) detect amplified production and compare the reagent that whether exists variation required, the 669th single nucleotide polymorphism in the sequence shown in the described SEQ ID NO:1 with normal kynurenine hydrolase gene.
Another kind of diagnostic kit comprises: the oligonucleotide probe that the primer that the present invention is above-mentioned and/or the present invention are above-mentioned.
The hypertensive test kit of another kind of diagnosis, it comprises: detect the active substrate of kynurenine hydrolase, described substrate is selected from: L-kynurenine and L-3-hydroxykynurenine.Preferably, described test kit also comprises and detects anthracene aniline and or the reagent of 3-hydroxyl anthracene aniline concentration.
Embodiment
The inventor is by extensive and deep research, the R188Q that has had been found that the kynurenine hydrolase gene is polymorphic, and (it is polymorphic to be that mRNA goes up G669A, or the G → A polymorphism at the 57th place of kynurenine hydrolase gene the 7th exon in the genome) in 6 familys and a kind of essential hypertension interlock in together, this hypertension incidence age early, pressure value is higher relatively, show that this sudden change may have influence on the function of gene, causes the rising of blood pressure.Finished the present invention on this basis.
Kynurenine hydrolase (abbreviating KYNU as) gene just in time is positioned at the core position to the full genome scanning result's of essential hypertension positive region, and the enzyme of the important metabolic pathway of KYNU genes encoding, relevant with the generation of the excitatory transmitter of maincenter, therefore be selected as candidate gene.
According to order-checking, 14 SNP have been found to normal people and each member's of essential hypertension family kynurenine hydrolase genome sequence.Find that by analysis wherein G → A the polymorphism and the essential hypertension at the 57th place of the 7th exon are chain, because this amino acid mutation causes 188 amino acids by Arg (R) → Gln (Q).Because this is the amino acid whose displacement of different properties, therefore, can cause the activity of kynurenine hydrolase to change (decline).Therefore, the SNP in this site in mRNA, cDNA that can be by detecting kynurenine hydrolase or the genomic dna, the perhaps enzymic activity by detecting kynurenine hydrolase among the patient (and compare with normal level), thus determine the diabetes susceptibility of object under inspection.
The cDNA sequence of kynurenine hydrolase gene is listed in SEQ ID NO:1, and wherein open reading frame is the 107-1501 position, and the aminoacid sequence of the kynurenine hydrolase of coding is listed in SEQ ID NO:2.The genome sequence of kynurenine hydrolase can obtain from GenBank.
Those skilled in the art will appreciate that a large amount of analytical technologies can be used for detecting whether the site exists single nucleotide polymorphism described in the kynurenine hydrolase gene.These technology comprise (but being not limited to): dna sequencing, sequencing by hybridization; Enzymatic mispairing cutting, heteroduple analysis, dot blot, oligonucleotide arrays (DNA chip), Mini-sequencing, Taqman technology, molecular beacon etc., sex change high performance liquid chromatography (DHPLC).
On the other hand, detection method of the present invention is used to assess the individual susceptibility of suffering from kynurenine hydrolase relative disease (especially essential hypertension).
Being used for specimen of the present invention and being not particularly limited, for detecting SNP, can be DNA or the mRNA that extracting goes out from samples such as blood, tissue.For detect kynurenine hydrolase active for, can anyly contain the sample of kynurenine hydrolase, as blood etc.
The primer and the probe that are used for the inventive method or detection kit design according to the cDNA sequence (sequence of SEQ ID NO:1) or the genome sequence of kynurenine hydrolase, and the synthetic technology of available routine is synthesized and got final product.
The enzymic activity detection method of kynurenine hydrolase is as known in the art.For example L-kynurenine and L-3-hydroxykynurenine carry out can to utilize its substrate.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, people such as Sambrook for example, molecular cloning: laboratory manual (New York:ColdSpring Harbor Laboratory Press, 1989) condition described in, or the condition of advising according to manufacturer.
Embodiment 1
The extracting of gene and order-checking
Extract DNA with conventional phenol chloroform method from people's blood, concentration correction is used for conventional pcr amplification to 20ng/ul.Primer is:
Adopted primer is arranged: 5 '-tca agg aga tcc crc tgt ttt C-3 ' (SEQ ID NO:3)
Antisense primer: 5 '-agg tcc ttc atg ctt tct tga-3 ' (SEQ ID NO:4)
The product of the 426bp that amplifies carries out dna sequencing behind the purifying.
Embodiment 2
The acquisition of SNP
Kynurenine hydrolase (abbreviating KYNU as) gene just in time is positioned at the core position to the full genome scanning result's of essential hypertension positive region, and the enzyme of the important metabolic pathway of KYNU genes encoding, relevant with the generation of the excitatory transmitter of maincenter, therefore brought direct order-checking.
Each sample sequence of measuring is compared, thereby draw the difference of sequence, obtain 14 kinds of SNP altogether.
Embodiment 3
The dependency of kynurenine hydrolase gene SNP and essential hypertension
In 14 kinds of SNP,, find that this SNP of G669A of kynurenine hydrolase gene is relevant with essential hypertension through the case-control analysis in the family of SNP and disease.The inventor has found 9 to be, can see that from these familys polymorphic and a kind of systolic hypertension of A of 669 interlocks in together, and the situation of exception can be explained with the difference of hypertensive heterogeneity and blood pressure degree.
| Tame number | Individual number | The 57th of the 7th exon | Height | Body weight | Systolic pressure | Diastolic pressure |
| 373 | 1 | A/G | 171 | 73 | 150 | 110 |
| 373 | 2 | A/G | 167 | 61 | 220 | 124 |
| 373 | 3 | A/G | 156 | 64 | 158 | 114 |
| 373 | 4 | A/G | 155 | 54 | 190 | 124 |
| 373 | 5 | A/G | 167 | 80 | 164 | 110 |
| 373 | 6 | G/G | 153 | 46 | 130 | 78 |
| 443 | 1 | A/G | 153 | 53 | 170 | 110 |
| 443 | 2 | A/G | 163 | 72 | 150 | 100 |
| 51 | 731 | A/G | 164 | 70 | 210 | 122 |
| 51 | 732 | G/G | 163 | 50 | 135 | 75 |
| 51 | 733 | G/G | 180 | 80 | 135 | 90 |
| 88 | 947 | A/G | 173 | 70 | 160 | 110 |
| 88 | 948 | A/G | 158 | 45 | 180 | 90 |
| 88 | 951 | A/G | 172 | 72 | 150 | 110 |
| 126 | 1160 | A/G | 153 | 65 | 190 | 100 |
| 126 | 1161 | G/G | 166 | 65 | 140 | 100 |
| 130 | 1178 | A/G | 174 | 74 | 170 | 100 |
| 130 | 1179 | A/G | 160 | 58 | 150 | 80 |
| 130 | 1180 | G/G | 170 | 70 | 140 | 100 |
| 123 | 1149 | A/G | 158 | 55 | 150 | 94 |
| 123 | 1150 | A/G | 173 | 71 | 140 | 100 |
| 11 | 546 | A/G | 170 | 75 | 180 | 120 |
| 11 | 547 | A/G | 156 | 62 | 150 | 110 |
| 11 | 548 | G/G | 165 | 75 | 150 | 105 |
| 11 | 549 | A/G | 170 | 65 | 135 | 90 |
| 11 | 550 | G/G | 158 | 52 | 136 | 90 |
| 515 | 1 | A/G | 161 | 78 | 164 | 80 |
| 515 | 2 | G/G | 172 | 80 | 156 | 100 |
| 515 | 3 | G/G | 161 | 61 | 124 | 80 |
| 515 | 4 | G/G | 173 | 80 | 118 | 80 |
| 515 | 5 | G/G | 157 | 82 | 134 | 90 |
| 515 | 6 | A/G | 156 | 69 | 170 | 88 |
Because this SNP frequency is lower, so searching for more big familys that may contain this SNP now.In addition, discover that this allelotrope may not be complete penetrance.
Embodiment 4
Detection kit
Preparation one detects the detection kit of hypertension susceptibility, and wherein, it is right to contain the following primer that amplifies 669 SNP:
Adopted primer is arranged: 5 '-tca agg aga tcc ctc tgt ttt c-3 ' (SEQ ID NO:3)
Antisense primer: 5 '-agg tcc ttc atg ctt tct tga-3 ' (SEQ ID NO:4)
Amplified production and normal control are carried out stratographic analysis with sex change high performance liquid chromatograph (DHPLC), can detect G → A type SNP of 669 easily.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Sequence table
＜110〉Nanfang Research Centre, State Human Gene Group
＜120〉kynurenine hydrolase polymorphism and diagnostic uses thereof
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Claims (6)
1. method that detects the single nucleotide polymorphism of people's kynurenine hydrolase gene is characterized in that it comprises step:
(a) determine the nucleotide sequence of the 57th of the 7th exon of people's kynurenine hydrolase gene in sample;
(b) detect whether there is single nucleotide polymorphism in described position.
2. the method for claim 1 is characterized in that, described single nucleotide polymorphism is the polymorphism that has G → A at the Nucleotide of the 57th of the 7th exon, promptly in the 669th polymorphism that has G → A corresponding to SEQ ID NO:1.
3. an isolating nucleic acid is characterized in that, the nucleotide sequence of described isolating nucleic acid is to be the sequence shown in the SEQ ID NO:1 the A except that the 669th.
4. one kind is used for the hypertensive test kit of auxiliary diagnosis, it is characterized in that it comprises:
(1) primer of specific amplification people kynurenine hydrolase gene is right, and the right sequence of wherein said primer is SEQ ID NO:3 and 4;
Whether (2) detect amplified production and compare with normal kynurenine hydrolase gene to exist and change required reagent, described variation is the 669th single nucleotide polymorphism in the sequence shown in the SEQ ID NO:1.
5. test kit as claimed in claim 4 is characterized in that, described test kit also comprises: detect the active substrate of kynurenine hydrolase, described substrate is selected from: L-kynurenine and L-3-hydroxykynurenine.
6. test kit as claimed in claim 5 is characterized in that, described test kit also comprises and detects anthracene aniline and or the reagent of 3-hydroxyl anthracene aniline concentration.
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101805784B (en) * | 2009-11-10 | 2013-02-13 | 首都医科大学附属北京安贞医院 | Single nucleotide polymorphism of human WNK4 genes and application thereof |
| CN113957061A (en) | 2013-08-30 | 2022-01-21 | 得克萨斯大学体系董事会 | Administration of kynurenine depleting enzymes for tumor therapy |
| JP7080053B2 (en) * | 2014-08-29 | 2022-06-03 | ボード オブ リージェンツ，ザ ユニバーシティ オブ テキサス システム | Administration of kynurenine-depleting enzymes for the treatment of tumors |
| EP3423483A4 (en) | 2016-03-02 | 2019-08-21 | Board Of Regents Of the University Of Texas System | Human kynureninase enzyme variants having improved pharmacological properties |
| EA202092487A1 (en) | 2018-04-16 | 2021-02-05 | Борд Оф Риджентс, Дзе Юниверсити Оф Техас Систем | HUMAN KINURENINASE ENZYMES AND THEIR APPLICATION |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1112786A (en) * | 1993-07-23 | 1995-11-29 | 药制品公司 | 2-amino-4-phenyl-4-oxo-butyric acid derivatives with kynureninase and/or kynurenine-3-hydroxylase inhibiting activity |
| CN1113386A (en) * | 1993-08-06 | 1995-12-13 | 巴尔的摩的马里兰大学 | Substituted kynurenines, a process for their preparation, and use as medicaments |
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2002
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1112786A (en) * | 1993-07-23 | 1995-11-29 | 药制品公司 | 2-amino-4-phenyl-4-oxo-butyric acid derivatives with kynureninase and/or kynurenine-3-hydroxylase inhibiting activity |
| CN1113386A (en) * | 1993-08-06 | 1995-12-13 | 巴尔的摩的马里兰大学 | Substituted kynurenines, a process for their preparation, and use as medicaments |
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