CN113981075A - Primer, probe composition and kit for detecting FGFR3 gene mutation site related to achondroplasia - Google Patents

Primer, probe composition and kit for detecting FGFR3 gene mutation site related to achondroplasia Download PDF

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CN113981075A
CN113981075A CN202111553217.1A CN202111553217A CN113981075A CN 113981075 A CN113981075 A CN 113981075A CN 202111553217 A CN202111553217 A CN 202111553217A CN 113981075 A CN113981075 A CN 113981075A
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蒋协远
苟默
邓微
魏星
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Beijing Jishuitan Hospital
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Abstract

The invention discloses a primer, a probe composition and a kit for detecting related FGFR3 gene variation sites of achondroplasia, wherein the related FGFR3 gene variation sites are a first site and a second site, the first site is NM-000142.5, exon10, c.1138G, A, p.Gly380Arg, and the second site is NM-000142.5, exon10, c.1138G, C, p.Gly380Arg; the nucleotide sequences of the upstream primers of the first site and the second site are shown as SEQ ID NO.1, and the nucleotide sequences of the downstream primers are shown as SEQ ID NO. 2; the nucleotide sequences of the wild probe of the first site and the wild probe of the second site are shown as SEQ ID NO.3, and the nucleotide sequence of the mutant probe of the first site is shown as SEQ ID NO. 4; the nucleotide sequence of the mutation probe of the second site is shown as SEQ ID NO. 5. The accuracy is higher, the false positive rate is lower, low cost, do not need high-end instrument, and the result is deciphered simply, is suitable for carrying out general screening, reduces the birth rate of achondroplasia infant.

Description

Primer, probe composition and kit for detecting FGFR3 gene mutation site related to achondroplasia
Technical Field
The invention belongs to the technical field of diagnosis of achondroplasia, and particularly relates to a primer, a probe composition and a kit for detecting FGFR3 gene variation sites related to achondroplasia.
Background
Achondroplasia (ACH) is the most common bone dysplasia, with an incidence of 1/77000-1/15000, belonging to autosomal dominant hereditary diseases with an exonic rate of 100%. Almost all cases of achondroplasia are caused by two pathogenic variations of the FGFR3 gene, namely c.1138g > a (accounting for about 98%) and c.1138g > C (accounting for about 1%), so detection of these two variations can aid in the diagnosis of 99% of achondroplasia patients. These two variants result in a change of glycine to arginine at position 380 of the transmembrane domain of FGFR3 (G380R), permanent activation of the FGFR3 receptor, inhibition of chondrocyte proliferation, and finally, impaired endochondral bone formation, restricted growth, shortened bone, and other skeletal abnormalities. About 80% -90% of cases of achondroplasia are caused by new (de novo) pathogenic mutations, which occur in older fathers, and another 10% -20% are due to familial inheritance.
Most patients with achondroplasia have normal intelligence and can live normally, and the death rate of the patients in infancy is about 2% -5%, mainly due to central asphyxia caused by the extrusion of the large-pore artery of the occipital bone. Most patients are accompanied by various complications, which place a great burden on life and spirit. Hydrocephalus may occur in patients with achondroplasia for the whole life, and the patients usually have thoracic vertebra kyphosis, vertebral pedicle shortening in adulthood leads to spinal canal stenosis, intervertebral disc protrusion and knee varus, and are accompanied with joint relaxation, muscle tension reduction, upper airway obstruction and sleep apnea of the whole body. The current clinical intervention method mainly aims at the complications and reduces the secondary damage generated by the complications. Early control and prevention of complications and great help to improve the life quality of patients.
Hormone therapy is commonly used clinically at present to relieve some complications of patients with achondroplasia. In 11 months 2020, FDA in the United states receives a New Drug Application (NDA) for the C-type natriuretic peptide analogue Vosolitide for the treatment of children's achondroplasia. A phase 3 study shows that Vosolitide is effective in promoting bone growth in children with achondroplasia and is still effective after one year. Vosoritide will be the first drug to treat achondroplasia if approved.
Gene testing is the gold standard for diagnosing achondroplasia. Clinical manifestations of achondroplasia and X-ray manifestations are often difficult to distinguish from hypoplasia (HCH) and Pseudoachondroplasia (PSACH), which are prone to misdiagnosis. Therefore, achondroplasia and similar hereditary dwarfism can be differentially diagnosed by detecting the existence of the mutation of the 1138 site of the FGFR3 gene. Meanwhile, achondroplasia is an autosomal dominant genetic disease which affects the development of a patient at an embryonic stage, the patient has obvious development defects on a skeletal system, and the dysplasia such as short stature and the like cannot be radically treated after birth, so that prenatal diagnosis and prenatal prevention of the child are very important. The prenatal screening and diagnosis method mainly comprises the steps of screening out a suspected fetus with short and small chondroplasia of long bones (namely humerus and femur) through fetal ultrasound, and then carrying out chromosome examination and FGFR3 gene 1138 locus variation detection on the screened suspected fetus with chondroplasia and an intrauterine growth retardation fetus (IUGR). However, the currently clinically used Sanger sequencing method is complex and time-consuming, and is difficult to meet the actual requirements, and a method for quickly, simply, conveniently and accurately detecting achondroplasia is lacking clinically.
Disclosure of Invention
Aiming at the problems that the Sanger sequencing method used clinically at present is complex and time-consuming and is difficult to meet the actual requirements, the invention provides a primer, a probe composition and a kit for detecting the site of the FGFR3 gene variation related to achondroplasia.
The technical scheme of the invention is as follows: a primer and a probe composition for detecting FGFR3 gene variation sites related to achondroplasia are provided, wherein the related FGFR3 gene variation sites are NM-000142.5, exon10, c.1138G, A, p.Gly380Arg and NM-000142.5, exon10, c.1138G, C, p.Gly380Arg;
the nucleotide sequences of the upstream primers of the primers are shown as SEQ ID NO.1, and the nucleotide sequences of the downstream primers are shown as SEQ ID NO. 2;
the probe comprises a first probe and a second probe;
the nucleotide sequence of the first probe is shown as SEQ ID NO. 4; the nucleotide sequence of the second probe is shown as SEQ ID NO. 5;
the 3' ends of the first probe and the second probe are both combined with a fluorescence quenching group; the 5' ends of the first probe and the second probe are respectively combined with a first fluorescent reporter group, a second fluorescent reporter group and a third fluorescent reporter group;
the first fluorescent reporter group, the second fluorescent reporter group and the third fluorescent reporter group interact with the fluorescent quenching group to generate a coordination compound which does not emit light.
Further defined, the fluorescence quencher group is MGB.
Further defined, the first fluorescent reporter is FAM.
Further defined, the second fluorescent reporter is VIC.
Further defined, the third fluorescent reporter is NED.
The invention also discloses a kit for detecting the FGFR3 gene variation site related to achondroplasia, which is characterized by comprising the primer and probe composition.
Further, the primers and probes for amplifying each mutation site in the kit exist in the form of a primer-probe mixture.
The kit is further defined to comprise a first PCR reaction system and a second PCR reaction system.
Further limiting, the first PCR reaction system is 20 μ L, and comprises 10 μ M, 1.8 μ L of upstream primer and downstream primer, 10 μ M, 0.4 μ L of wild probe, 10 μ M, 0.6 μ L of first probe, 10 μ L of qPCR reaction buffer, 2 μ L of DNA solution to be tested and 1-15ng/μ L of ddH before adding into the system2The volume of O was 3.4. mu.L.
10. The kit of claim 8, wherein the second PCR reaction system is 20 μ L, and comprises 10 μ M and 1.8 μ L of the forward primerAnd downstream primer, 10 mu M, 0.2 mu L wild probe, 10 mu M, 0.6 mu L second probe, 10 mu L qPCR reaction buffer solution, 2 mu L DNA solution to be detected and 1-15 ng/mu L ddH before adding into the system2The volume of O was 3.4. mu.L.
Has the advantages that: the kit provided by the invention is a fluorescence quantitative PCR method based on a Taqman probe, and has the advantages of higher accuracy, lower false positive rate, low cost, no need of high-end instruments, simple result interpretation, suitability for universal screening and reduction of the birth rate of children with achondroplasia.
Drawings
FIG. 1 is a graph of the results of Log Log curve experiments using wild type DNA as a template;
FIG. 2 is a graph showing the results of a Linear amplification Curve experiment using wild type DNA as a template;
FIG. 3 is a graph of Log curve experimental results when using the variant site carrier DNA of FGFR3 gene NM-000142.5: exon10: c.1138G > A as a template;
FIG. 4 is a graph of the results of a Linear amplification curve experiment using FGFR3 gene NM-000142.5: exon10: c.1138G > A variant site carrier DNA as a template;
FIG. 5 is a graph of the results of Log curve experiments using wild-type DNA as a template;
FIG. 6 is a graph showing the results of a Linear amplification Curve experiment using wild type DNA as a template;
FIG. 7 is a graph of Log curve experimental results when using the variant site carrier DNA of FGFR3 gene NM-000142.5: exon10: c.1138G > C as a template;
FIG. 8 is a graph showing the results of a Linear amplification curve experiment using the FGFR3 gene NM-000142.5: exon10: c.1138G > C variant site carrier DNA as a template.
Detailed Description
Example 1
The embodiment relates to a kit for detecting a mutation site of an FGFR3 gene related to achondroplasia, which comprises a PCR reaction system for detecting the mutation site of NM-000142.5: exon10: c.1138G > A: p.Gly380Arg and a PCR reaction system for detecting the mutation site of NM-000142.5: exon10: c.1138G > C: p.Gly380Arg. A mutation probe shared by the two mutation sites is called a probe WT for short, a mutation probe of NM-000142.5: exon10: c.1138G > A: p.Gly380Arg is called a probe Mut1 for short, and a mutation probe of NM-000142.5: exon10: c.1138G > C: p.Gly380Arg is called a probe Mut2 for short.
The primers for the DNA template containing the mutation site NM-000142.5: exon10: c.1138G > A: p.Gly380Arg and the DNA template containing the mutation site NM-000142.5: exon10: c.1138G > C: p.Gly380Arg are shown in Table 1, and the probes for the mutation site are shown in Table 2.
TABLE 1 primers
Figure BDA0003418307840000051
TABLE 2 Probe
Figure BDA0003418307840000052
Figure BDA0003418307840000061
1. The system configuration for detecting NM-000142.5: exon10: c.1138G > A: p.Gly380Arg is shown in Table 3:
TABLE 3
Components Volume uL Final concentration (μ M)
Upstream primer (10. mu.M) 1.8 900
Downstream primer (10. mu.M) 1.8 900
Probe WT (10 μ M) 0.4 200
Probe Mut1 (10. mu.M) 0.6 300
qPCR reaction buffer 10 -
Template DNA solution (1-15 ng/. mu.L) 2 -
RNase-free ddH2O 3.4 -
Total volume 20 -
The amplification procedure is shown in table 4:
TABLE 4
Figure BDA0003418307840000062
Figure BDA0003418307840000071
2. The system configuration for detecting NM-000142.5: exon10: c.1138G > C: p.Gly380Arg is shown in Table 5:
TABLE 5
Components Volume uL Final concentration (μ M)
Upstream primer (10. mu.M) 1.8 900
Downstream primer (10. mu.M) 1.8 900
Probe WT (10 μ M) 0.2 100
Probe Mut2 (10. mu.M) 0.8 400
qPCR reaction buffer 10 -
Template DNA solution(1-15ng/μL) 2 -
RNase-free ddH2O 3.4 -
Total volume 20 -
The amplification procedure is shown in table 5:
TABLE 5
Figure BDA0003418307840000072
The PCR amplification results were as follows:
3.1 Using wild-type DNA as template, the results are shown in Table 6:
TABLE 6
Figure BDA0003418307840000081
In table 6, the samples (WT1, WT2, WT3, WT4, WT5) are wild-type human genomic DNA, the threshold lines of FAM and VIC signals are set to 0.5, and it can be seen from table 6 that the Ct value difference between FAM and VIC channels is greater than 10.0. The Log curve experiment result is shown in FIG. 1, and the Linear amplification curve experiment result is shown in FIG. 2:
3.2 when FGFR3 gene NM _000142.5: exon10: c.1138g > a variant site carrier DNA was used as template:
TABLE 7
Figure BDA0003418307840000082
Figure BDA0003418307840000091
The samples (CT1, CT2, CT3, CT4 and CT5) in the table 7 are FGFR3 gene NM-000142.5: exon10: c.1138G > A mutation site carrier DNA, and the threshold lines of FAM and VIC signals are set to be 0.5. As can be seen from Table 7, the difference between the Ct values of both the FAM channel and the VIC channel is not greater than 1.0. The Log logarithmic curve experimental result is shown in figure 3, the Linear amplification curve experimental result is shown in figure 4, and the Linear amplification curves of the two alleles are basically overlapped with the increase of the cycle times, so that the kit has high detection accuracy on the FGFR3 gene NM-000142.5: exon10: c.1138G > A mutation sites.
In summary, after the reaction is finished, FAM and VIC fluorescence channel Threshold values are set to 0.5, and Analyze is clicked for analysis. When the detected DNA sample is a wild type, the difference of Ct values between the two channels is more than 10.0; when the detected sample is a heterozygous mutant type, the difference of Ct values between two channels is less than 1.0.
4. When using the system for detecting NM-000142.5: exon10: c.1138G > C: p.Gly380Arg
4.1 when wild-type DNA is used as template:
TABLE 8
Figure BDA0003418307840000092
Figure BDA0003418307840000101
In table 8 where the samples (WT1, WT2, WT3, WT4, WT5) are wild-type human genomic DNA, the threshold lines for FAM and NED signals were set to 0.5. As can be seen from Table 8, the Ct values for both FAM and NED channels were greater than 10.0.
The Log curve experiment results are shown in FIG. 5, and the Linear amplification curve experiment results are shown in FIG. 6.
4.2 when FGFR3 gene NM _000142.5: exon10: c.1138g > C variant site carrier DNA was used as template:
TABLE 9
Figure BDA0003418307840000102
The samples (CG1, CG2, CG3, CG4 and CG5) in the table are FGFR3 gene NM-000142.5: exon10: c.1138G > C mutation site carrier DNA, and the threshold line of FAM and NED signals is set to be 0.5. As can be seen from the above table, the difference between the Ct values of the FAM channel and the NED channel is not greater than 1.0.
The Log logarithmic curve experimental result is shown in figure 7, the Linear amplification curve experimental result of Linear amplification is shown in figure 8, and the Linear amplification curves of two alleles are basically overlapped with the increase of the cycle times, so that the kit has high detection accuracy on the FGFR3 gene NM-000142.5: exon10: c.1138G > C mutation sites.
In summary, after the reaction is completed, FAM and NED fluorescence channel Threshold values are set to 0.5, and Analyze is clicked for analysis. When the detected DNA sample is a wild type, the difference of Ct values between the two channels is more than 10.0; when the detected sample is a heterozygous mutant type, the difference of Ct values between two channels is less than 1.0.
Finally, it should be noted that: the above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (9)

1. A primer and a probe composition for detecting FGFR3 gene variation sites related to achondroplasia are characterized in that the nucleotide sequences of the upstream primers of the primer are shown as SEQ ID NO.1, and the nucleotide sequences of the downstream primers are shown as SEQ ID NO. 2;
the probe comprises a first probe and a second probe;
the nucleotide sequence of the first probe is shown as SEQ ID NO. 4; the nucleotide sequence of the second probe is shown as SEQ ID NO. 5;
the 3' ends of the first probe and the second probe are both combined with a fluorescence quenching group; the 5' ends of the first probe and the second probe are respectively combined with a first fluorescent reporter group, a second fluorescent reporter group and a third fluorescent reporter group;
the first fluorescent reporter group, the second fluorescent reporter group and the third fluorescent reporter group interact with the fluorescent quenching group to generate a coordination compound which does not emit light.
2. The primer and probe composition of claim 1, wherein the fluorescence quenching group is MGB.
3. The primer and probe composition of claim 1 or 2, wherein the first fluorescent reporter is FAM.
4. The primer and probe composition of claim 3, wherein the second fluorescent reporter group is VIC.
5. The primer and probe composition of claim 4, wherein the third fluorescent reporter is NED.
6. A kit for detecting a site of a mutation in FGFR3 gene related to achondroplasia, which comprises the primer and probe composition according to any one of claims 1 to 5.
7. The kit of claim 6, wherein the kit comprises a first PCR reaction system and a second PCR reaction system.
8. The kit of claim 7, wherein the first PCR reaction system is 20 μ L, and comprises 10 μ M, 1.8 μ L of the upstream primer and the downstream primer, 10 μ M, 0.4 μ L of the wild probe, 10 μ M, 0.6 μ L of the first probe, 10 μ L of qPCR reaction buffer, 2 μ L of the DNA solution to be tested and 1-15 μ L of the concentration before adding into the systemng/μL，ddH2The volume of O was 3.4. mu.L.
9. The kit of claim 7, wherein the second PCR reaction system is 20 μ L, and comprises 10 μ M, 1.8 μ L of the upstream primer and the downstream primer, 10 μ M, 0.2 μ L of the wild probe, 10 μ M, 0.6 μ L of the second probe, 10 μ L of qPCR reaction buffer, 2 μ L of the DNA solution to be tested and 1-15ng/μ L of ddH before adding into the system, and the concentration of ddH is 1-15ng/μ L2The volume of O was 3.4. mu.L.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103789416A (en) * 2014-01-04 2014-05-14 杭州艾迪康医学检验中心有限公司 Method and oligonucleotide for detecting FGFR3 gene G380R site mutation
CN111424081A (en) * 2020-04-13 2020-07-17 广东省妇幼保健院 Primer, probe and kit for detecting chondroplast FGFR3 gene mutation based on multiple fluorescent quantitative PCR technology

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103789416A (en) * 2014-01-04 2014-05-14 杭州艾迪康医学检验中心有限公司 Method and oligonucleotide for detecting FGFR3 gene G380R site mutation
CN111424081A (en) * 2020-04-13 2020-07-17 广东省妇幼保健院 Primer, probe and kit for detecting chondroplast FGFR3 gene mutation based on multiple fluorescent quantitative PCR technology

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BELLUS G.A.等: "Achondroplasia is defined by recurrent G380R mutations of FGFR3" *
ETLIK O.等: "An improved tetra-primer PCR approach for the detection of the FGFR3 G380R mutation responsible for achondroplasia" *
HUNG C.C.等: "Genotyping of the G1138A mutation of the FGFR3 gene in patients with achondroplasia using high-resolution melting analysis" *
何书励 等: "FGFR3基因G1138A突变导致软骨发育不全" *

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Application publication date: 20220128