CN104650214B - Pulmonary hypertension Disease-causing gene ACVRL1 mutational sites and its application - Google Patents
Pulmonary hypertension Disease-causing gene ACVRL1 mutational sites and its application Download PDFInfo
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Abstract
The invention discloses pulmonary hypertension Disease-causing gene ACVRL1 mutational sites and its application.A kind of albumen that the present invention is provided, its amino acid sequence is sequence 4.The DNA molecular of above-mentioned albumen is encoded, its nucleotides sequence is classified as sequence 2.The experiment proves that, present invention discover that a kind of new ACVRL1 gene mutation sites, it is related to pulmonary hypertension, by detecting whether as the mutational site, predict whether sample to be tested suffers from pulmonary hypertension, it can provide new therapy approach as the target spot for treating pulmonary hypertension for research pulmonary hypertension medicine in the future.And verified by cell experiment, ACVRL1 gene mutation sites can reduce in cell SMAD1 and SMAD5 protein phosphorylations and/or improve BMP transcriptional activities in cell.
Description
Technical field
The present invention relates to biological technical field, more particularly to pulmonary hypertension Disease-causing gene ACVRL1 mutational sites and its should
With.
Background technology
Pulmonary hypertension (Pulmonary Arterial Hypertension, PAH) is a kind of serious disease of extreme.
Although the application of the new treatment such as some new medicines and gene therapy, live body lung transplantation, atrial septum fistulization, makes patient 5 in recent years
Year or 10 annual survival rates are improved, but are relief of symptoms its therapeutic scheme more, and can not change the process and clinic of disease
Consequence.One of major reason is that PAH pathogenic mutation is not fully apparent from also, and the relation of its pathogenesis and clinical phenotypes is also
Not yet explicitly.Bone morphogenetic protein2 receptor, serotonin, Serotonin Transporter, prostacyclin receptor, prostacyclin synthase, electricity
Potassium channel, nitric oxide, the endothelin -1 of pressure gate control, the gene coding region such as ETA, B acceptors and active oxygen changes
Change all may be relevant with PAH formation.Therefore, the understanding regulated and controled to above-mentioned protein gene, it will help more deep recognizes
Know the PAH cause of disease, prognosis and treatment etc..
Identification PAH Disease-causing gene and the method for mutation is candidate gene approach earliest, it is impossible to determine causing a disease for disease completely
Gene.And new-generation sequencing technology is carried out for whole extron group or target area interested (being recognized by early-stage Study)
High-flux sequence, can study interaction relationship complicated between gene and gene, it can be found that new pathogenic mutation, is finding
(including rare SNPs and structural variation) also show obvious advantage in terms of the hereditary information not yet disclosed.Therefore, pass through
Target area capture sequencing remove examination PAH known to pathogenic mutation, be that patient makes gene diagnosis.Known pathogenic mutation is such as investigated
The negative PAH familys of collection known mutations, set up queue, carry out the gene sequencing of full extron, search is isolated with disease
Pathogenic new mutation.
The content of the invention
It is an object of the present invention to provide a kind of albumen.
The albumen that the present invention is provided, its amino acid sequence is sequence 4.
The DNA molecular for encoding above-mentioned albumen is also the scope of protection of the invention, and its nucleotides sequence is classified as sequence 2.
Recombinant vector, expression cassette, transgenic cell line or recombinant bacterium containing above-mentioned DNA molecular are also that the present invention is protected
Scope.
Above-mentioned transgenic cell does not include plant propagation material.
Above-mentioned albumen or above-mentioned DNA molecular are following 1) -4) at least one of in application be also protection of the present invention
Scope：
1) SMAD1 and SMAD5 protein phosphorylations in reduction cell；
2) BMP transcriptional activities in cell are improved；
3) SMAD1 and SMAD5 protein phosphorylation products in reduction cell are prepared；
4) prepare and improve BMP transcriptional activity products in cell.
In above-mentioned application, the cell is NIH3T3 cells.
The system that whether is mutated of ACVRL1 genes in detection receptor gene's group DNA prepare prediction or auxiliary prediction by
The application whether examination person suffers from the product of pulmonary hypertension is also the scope of protection of the invention.
In above-mentioned application, the system whether the ACVRL1 genes in the detection sample to be tested genomic DNA are mutated includes
Sequencing primer；
The system also includes the instrument and/or reagent needed for DNA is sequenced, such as sequenator.
The sequencing primer is as single-stranded shown in sequence 6 in the single strand dna shown in sequence in sequence table 5 and sequence table
DNA molecular is constituted.
In above-mentioned application, the kit whether the ACVRL1 genes in the detection receptor gene group DNA are mutated also is wrapped
Include the standard recorded on readable carrier：
The standard is as follows：
If subject ACVRL1 genes are wild type ACVRL1 genes, the subject does not suffer from pulmonary hypertension or candidate not
Suffer from pulmonary hypertension；If subject ACVRL1 genes are saltant type ACVRL1 genes, the subject suffers from pulmonary hypertension or time
Pulmonary hypertension is suffered from choosing.
The nucleotides sequence of the wild type ACVRL1 genes is classified as sequence 1 in sequence table；
The nucleotides sequence of the saltant type ACVRL1 genes is classified as sequence 2, and the sequence 2 is to replace the 955th G of sequence 1
C is changed to, the sequence that remaining invariant nucleotide is obtained.
In above-mentioned application, whether the ACVRL1 genes sport the 955th of the ACVRL1 gene nucleotide series 1
Whether nucleotides sports C by G.
G is wild type, and C is saltant type.
In above-mentioned application, the subject is member in the family of pulmonary hypertension medical history.
Whether it is mutated it is a further object to provide a kind of ACVRL1 genes detected in receptor gene's group DNA
System.
The system that the present invention is provided, is the system in above-mentioned application.
Whether the ACVRL1 genes are mutated the 955th nucleotides of specially described ACVRL1 gene nucleotide series 1
Whether C is sported by G.
In view of merging the possible poor prognosis of ACVRL1 gene mutations PAH, PAH patient, especially heredity are tackled
PAH, idiopathic PAH and patient and the relatives' row detection in Gene Mutation for merging HHT, are asymptomatic relatives to make a definite diagnosis lesion ahead of time
The prediction of initiation potential degree is provided significant, to merging the potential hair patient being mutated, it is proposed that every 3 years check echocardiograms,
With reference to the close observation of clinical symptoms, early diagnosis and intervention to PAH are of great importance with improving clinical prognosis.To children
PAH patient, also should actively row genetic test is with as early as possible for the clearly offer foundation of the cause of disease, detection parents are to have found to carry pathogenic base
Because of the high risk person of mutation, while determining father and mother's ill risk of row fertility offspring again.
The experiment proves that, present invention discover that a kind of new ACVRL1 gene mutation sites, itself and pulmonary hypertension
Correlation, by detecting whether as the mutational site, whether prediction sample to be tested suffers from pulmonary hypertension, and it can be used as treatment lung
The target spot of arterial hypertension, new therapy approach is provided for research pulmonary hypertension medicine in the future.And verified by cell experiment,
ACVRL1 gene mutation sites can reduce in cell SMAD1 and SMAD5 protein phosphorylations and/or improve BMP in cell and transcribe
Activity.
Brief description of the drawings
Fig. 1 is pedigree chart
Fig. 2 is Sanger sequencing results
Fig. 3 is SMAD1/5 phosphorylation level testing results after cell transfecting related plasmids
Fig. 4 is BMP-9 transcriptional activities detection after cell transfecting related plasmids
Embodiment
Experimental method used in following embodiments is conventional method unless otherwise specified.
Material, reagent used etc., unless otherwise specified, are commercially obtained in following embodiments.
DNA extraction kit：QIAGEN companies, catalog number is D0161.
NEBNextDNA libraries reagent preparation box：NEB companies, catalog number is D0089.
GenCap gene order capture agent boxes：GenCap companies, catalog number is L2880.
Whether embodiment 1, ACVRL1 genes are mutated the application in identifying whether sample to be tested is patients with pulmonary hypertension
System on the right side of a certain patients with pulmonary hypertension sample pedigree chart to be measured such as Fig. 1 (I.2, II.2, III.4, III.5,
III.6, III.7, III.8, IV.4, IV.5, IV.6) shown in, wherein patients with pulmonary hypertension be 3 (III.5, III.7,
IV.4), remaining is non-patients with pulmonary hypertension.
ACVRL1 gene mutation knots in each sample in Sanger sequence verifications patients with pulmonary hypertension sample family to be measured
Really, it is specific as follows：
1st, sample to be tested anticoagulated whole blood is taken, genomic DNA is extracted using QIAGEN companies DNA extraction kit；
2nd, genomic DNA is sent into Sanger sequencings
Sequencing primer is as follows：
c.955G>C F-ACGACTCCAGCCTCCCTTAG (sequence 5)
c.955G>C R-AGACAACTCGTGGGGTCTTG (sequence 6)
As a result as shown in fig. 2, it can be seen that
Sample 1.2,11.2, III.4, III.6, III.8, IV5, IV6 are wild type ACVRL1 genes, and its nucleotides is sequence
Sequence 1 in list, its protein amino acid sequence encoded is sequence 3；
Sample III.5, III.7, IV.4 are saltant type ACVRL1 genes, and its nucleotides sequence is classified as sequence 2, for by sequence 1
955th G replaces with C, the sequence that remaining invariant nucleotide is obtained；Its protein amino acid sequence encoded is sequence 4, sequence 4
For the 319th of sequence 3 Gly glycine is changed into Arg arginine；
Part sample ACVRL1 gene informations are as shown in table 1：
Table 1 is part sample ACVRL1 gene informations
From the above, it can be seen that can be by detecting whether family member's ACVRL1 genes of pulmonary hypertension medical history are mutated
Auxiliary predicts whether the member suffers from pulmonary hypertension, and specific method is as follows：
If the member ACVRL1 of this in family genes are wild type ACVRL1 genes (sequence 1), the member does not suffer from pulmonary artery
High pressure or candidate do not suffer from pulmonary hypertension；If the member ACVRL1 of this in family genes be saltant type ACVRL1 genes (sequence 2,
955G>C), then the member suffers from pulmonary hypertension or candidate suffers from pulmonary hypertension.
The application of embodiment 2, ACVRL1 mutains
1st, ACVRL1 wild plasmids and mutant plasmids are prepared
ACVRL1 wild plasmids are that sequence in sequence table 1 is inserted into pcDNA3.1 carriers (Addgene companies, #20011)
EcoR1 and BamHI sites between obtained carrier.
ACVRL1 mutant plasmids be by sequence in sequence table 2 (be that the G of sequence 1 the 955th is replaced with into C, other nucleosides
Acid is constant) obtained carrier between EcoR1 the and BamHI sites of insertion pCDNA3.3 carriers.
2nd, SMAD1/5 phosphorylation level detections are carried out using plasmid
TGF-β acceptor belongs to cell surface receptor, including two classes --- and I types and II types, there is serine kinase to urge for its own
Change domain, when part TGF-β is in combination, the effect of generation makes the important transcription factor Smad families silk ammonia of the class of downstream one
Phosphorylation occurs for acid.Activin receptor-like kinases 1 (ACVRL1/ALK1) are made up of 503 amino acid, belong to TGF-β I receptors
One kind (other 6 I type TGF-β acceptors are respectively designated as ACVRL2-7).When ligand binding TGF-β acceptor, II receptors
First activate after phosphorylation activation I receptors (including ACVRL1, ACVRL2, ACVRL3 or ACVRL6) and therewith formed acceptor answer
Compound.The receptor complex of activation makes the Smad1/5/8 in downstream be activated, and then activates Smad4 and formation in combination is homologous
Enter nucleus after oligomer or hetero-oligomer, adjust the transcription speed of corresponding gene, finally influence cell differentiation
By ACVRL1 wild plasmids and ACVRL1 mutant plasmids difference rotaring copolymering NIH 3 T 3 cell, transfection reagent box：
The article No. 11668-019 of Invitrogen liposomes 2000, obtains transfection ACVRL1 wild plasmids cell (WT) and transfection
ACVRL1 mutant plasmids cell (G319R).
1 day after transfection, after cell is stimulated 1 hour through 100pg/ml BMP-9, PIERCE companies M-PER lysates are utilized
(article No.：78501) cell lysis, carries out Western Blot (Cell Signal companies phosphorylation SMAD1/5 antibody, #
9516S), detection SMAD1/5 (SMAD1 protein amino acid sequences are sequence 7, and SMAD5 protein amino acid sequences are sequence 8) phosphoric acid
Change.
As a result fig. 3, it is shown that BMP-9 stimulate after, with transfection ACVRL1 mutant plasmids cell (G319R)
Compare, phosphorylation SMAD1/5 substantially increases in transfection ACVRL1 wild plasmid cells.
5th, BMP transcriptional activity detections are carried out using plasmid,
By ACVRL1 wild plasmids and BRE-luc plasmids (pGL3BRE luciferase, ADDGENE, article No.：
45126) cotransfection NIH3T3 cells, obtain transfection ACVRL1 wild plasmids cell (WT).
By ACVRL1 mutant plasmids and BRE-luc plasmids (pGL3BRE luciferase, ADDGENE, article No.：
45126) cotransfection NIH3T3 cells, obtain transfection ACVRL1 mutant plasmids cell (G319R).
4 hours after transfection, after cell is stimulated 16 hours through 100pg/ml BMP-9, luciferase detection (fluorescence is carried out
Plain zymolyte PEL article No.s 122796, renilla luciferase substrate PEL article No.s 760506), then Caliper imaging systems100 detection BMP (sequence 9) transcriptional activity.
As a result such as Fig. 4, it can be seen that after BMP-9 is stimulated, compared with transfection ACVRL1 mutant plasmids cell (G319R),
BMP transcriptional activities substantially increase in transfection ACVRL1 wild plasmid cells.
Claims (10)
1. a kind of albumen, its amino acid sequence is sequence 4.
2. encode the DNA molecular of albumen described in claim 1.
3. DNA molecular according to claim 2, it is characterised in that：The nucleotides sequence of the DNA molecular is classified as sequence 2.
4. recombinant vector, expression cassette or recombinant bacterium containing DNA molecular described in Claims 2 or 3.
5. the DNA molecular described in albumen or Claims 2 or 3 described in claim 1 is following 1）-4）At least one of in
Using：
1）Reduce SMAD1 and SMAD5 protein phosphorylations in cell；
2）Reduce BMP transcriptional activities in cell；
3）Prepare SMAD1 and SMAD5 protein phosphorylation products in reduction cell；
4）Prepare BMP transcriptional activity products in reduction cell；
The application is non-diseases diagnoses and treatment application.
6. application according to claim 5, it is characterised in that：The cell is NIH3T3 cells.
7. the system whether the ACVRL1 genes in detection receptor gene's group DNA are mutated is preparing prediction or is aiding in prediction tested
Whether person suffers from the application in the product of pulmonary hypertension, it is characterised in that：By detect ACVRL1 gene nucleotide series 1
Whether 955 nucleotides determines whether the ACVRL1 genes are mutated by G sports C.
8. application according to claim 7, it is characterised in that：ACVRL1 bases in the detection receptor gene group DNA
Because whether the system being mutated includes sequencing primer；The sequencing primer is as the single strand dna and sequence shown in sequence in sequence table 5
Single strand dna composition in list shown in sequence 6.
9. the application according to claim 7 or 8, it is characterised in that：The subject is the family of pulmonary hypertension medical history
Middle member.
10. it is to appoint in claim 7-9 a kind of system for whether being mutated of ACVRL1 genes detected in receptor gene's group DNA
The system in application described in one,
It is characterized in that：By detecting the 955th nucleotides of ACVRL1 gene nucleotide series 1 whether by G sports C come really
Whether the fixed ACVRL1 genes are mutated.
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| CN106086190A (en) * | 2016-06-23 | 2016-11-09 | 北京市心肺血管疾病研究所 | Detect reagent set and method that whether pulmonary hypertension related gene undergos mutation |
| CN107760779B (en) * | 2017-11-03 | 2020-10-16 | 中国医学科学院阜外医院 | Mutant BMP9 gene related to pulmonary hypertension and application thereof |
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| Title |
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| Clinical features of pulmonary arterial hypertension in young people with an ALK1 mutation and hereditary haemorrhagic telangiectasia;L B Smoot等;《Arch Dis Child》;20090408;第94卷;第506-511页 * |
| Clinical Outcomes of Pulmonary Arterial Hypertension in Patients Carrying an ACVRL1 (ALK1) Mutation;Barbara Girerd等;《AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE》;20100107;第181卷(第8期);第856页右栏第2段，表5 * |
| Functional analysis of the BMP9 response ofALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations;Nicolas Ricard等;《VASCULAR BIOLOGY：BLOOD》;20100325;第116卷(第9期);第1604-1612页 * |
| Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia;R E Harrison等;《J Med Genet》;20031231;第40卷;第865-871页 * |
| Novel Mutations in BMPR2, ACVRL1 and KCNA5 Genes and Hemodynamic Parameters in Patients with Pulmonary Arterial Hypertension;Guillermo Pousada等;《PLOS ONE》;20140617;第9卷;第1-10页 * |
| Smad Signaling in the Rat Model of Monocrotaline Pulmonary Hypertension;MARGARET F.RAMOS等;《Toxicologic Pathology》;20081231;第36卷;第311-320页 * |
| 肺动脉高压发生机制及治疗药物的研究进展;宋洁梅等;《中国药科大学学报》;20131231;第44卷(第1期);第1-10页 * |
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