CN111304314B - Application of ZNF124 gene in early screening or auxiliary diagnosis of retinitis pigmentosa diseases - Google Patents
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Abstract
The invention discloses an application of ZNF124 gene in early screening or auxiliary diagnosis of retinitis pigmentosa diseases, and relates to the technical field of gene detection. The invention discloses an application of a detection reagent for detecting ZNF124 gene mutation in preparation of a reagent or a kit for early screening or auxiliary diagnosis of retinitis pigmentosa diseases. The research of the invention discovers that the mutation of the ZNF124 gene is related to the retinal pigment degeneration disease, and the detection of the mutation of the ZNF124 gene can be used for carrying out early screening on the retinal pigment degeneration disease or carrying out auxiliary diagnosis on the retinal pigment degeneration disease, thereby providing a new scheme for the early screening or diagnosis of the retinal pigment degeneration disease.
Description
Technical Field
The invention relates to the technical field of gene detection, in particular to application of ZNF124 gene in early screening or auxiliary diagnosis of retinitis pigmentosa diseases.
Background
Retinitis Pigmentosa (RP) is an inherited retinal disease caused by abnormalities in photoreceptor cells, including rod and cone cells. The worldwide incidence of RP is about 1/5000-1/3500; in China, the incidence rate of RP is also rising year by year, about l/l000, and is one of the important reasons for blindness. The typical RP patients first develop night blindness and visual field stenosis due to rod cell function defects, gradually developing into tubular visual fields until blindness; retinal pigmentation was visible by fundus examination. The pathogenesis of RP is abnormally complex, involving a number of different biological metabolic pathways. The protein coded by the pathogenic gene is mainly involved in the processes of light conduction, maintenance of a photoreceptor cell structure, mRNA splicing and the like. Impairment of protein function due to mutation of genes encoding various proteins in different biological pathways may lead to abnormality of photoreceptor cells, resulting in the occurrence of RP. Pathologically, the classical RP affects predominantly rod cells, causing rod cell death and secondary cone cell death, mainly manifested by photoreceptor damage, degeneration, progressive thinning of the outer retinal nuclear layer until it disappears, and corresponding pathological changes in the outer retinal layer and other related cell layers.
RP has a significant genetic predisposition. RP can be divided mainly into autosomal dominant RP (adrP: 15-25%), autosomal recessive RP (arrP: 5-25%) and X-linked RP (XLRP: 10-15%) according to genetic methods. In addition to this, there are some rare atypical mendelian inheritance patterns of RP, such as two-gene inheritance, mitochondrial inheritance, Y-linked inheritance, and the like. At present, 70 gene mutations are reported to be related to RP, but only about 50% of cases can be explained, and a part of pathogenic genes are not found yet. Therefore, further searching and expanding RP related pathogenic genes and mutations thereof are important for early screening and prevention and control of RP.
Disclosure of Invention
The invention aims to provide the application of ZNF124 gene in early screening or auxiliary diagnosis of retinitis pigmentosa diseases. The research of the invention discovers that the mutation of the ZNF124 gene is related to the retinal pigment degeneration disease, and the detection of the mutation of the ZNF124 gene can be used for carrying out early screening on the retinal pigment degeneration disease or carrying out auxiliary diagnosis on the retinal pigment degeneration disease, thereby providing a new scheme for the early screening or diagnosis of the retinal pigment degeneration disease.
The invention is realized by the following steps:
in a first aspect, the embodiments of the present invention provide an application of a detection reagent for detecting a mutation of ZNF124 gene in preparing a reagent or a kit for early screening or auxiliary diagnosis of retinitis pigmentosa diseases.
The ZNF124 gene is a novel gene for coding zinc finger protein. Zinc finger proteins are transcription factors with finger-like domains, and play an important role in gene regulation. ZNF124 protein can enter nucleus through nuclear pore and can be used as transcription factor to regulate the expression of other genes. The research of the invention discovers that the ZNF124 gene mutation can cause the retinal pigment degeneration disease, the ZNF124 gene mutation is related to the retinal pigment degeneration disease, and the detection of the ZNF124 gene mutation can carry out early screening or auxiliary diagnosis on the retinal pigment degeneration disease; therefore, the invention provides a new application of the detection reagent for detecting the ZNF124 gene mutation, and the detection reagent can be used for preparing a reagent or a kit for early screening or auxiliary diagnosis of the retinal pigment degeneration disease and provides a new detection means for the early screening or the diagnosis of the retinal pigment degeneration disease.
In alternative embodiments, the detection reagent detects a mutation in the ZNF124 gene comprising: c.219-1G-.
According to the invention, exon sequencing is carried out on two RP family members, and the exon4 (exon 4) of the ZNF124 gene (NM _003431) of the member with retinitis pigmentosa disease in the RP family has homozygous deletion mutation c.219-1G < - >, namely, compared with a normal individual, the G of the member with retinitis pigmentosa disease at the 1 st position upstream of the 219 th base of the coding region of the gene is deleted, and the 219 th base is just the first position of the exon 4. The specific mutation positions are shown below, with exon sequences underlined, and the first italic letter underlined in the fourth place as the mutation site:
in addition, the mutation was not detected in 3000 control samples. Accordingly, it is well believed that the homozygous deletion mutation c.219-1G-occurring on the ZNF124 gene is an important causative factor of retinal pigment degeneration diseases, and thus, early screening or diagnosis of retinal pigment degeneration diseases can be performed by detecting the mutation c.219-1G-.
In alternative embodiments, the detection reagent is selected from any one or a combination of the following methods suitable for detecting a ZNF124 gene mutation: restriction fragment length polymorphism (PCR-RFLP), Denaturing Gradient Gel Electrophoresis (DGGE), allele specific PCR, DNA sequencing, DNA chip detection, Time of Flight Mass spectrometry (TOF), and single strand conformation polymorphism analysis (SSCP).
In alternative embodiments, the DNA sequencing method is whole exon sequencing or Sanger sequencing.
It should be noted that there are many methods or techniques for detecting gene mutation in the art, including but not limited to the restriction fragment length polymorphism (PCR-RFLP) method, Denaturing Gradient Gel Electrophoresis (DGGE), allele specific PCR, DNA sequencing, DNA chip detection, Time of Flight Mass spectrometry (TOF), single strand conformation polymorphism analysis (SSCP), etc., and based on the gene sequence and the type of mutation to be detected disclosed in the present invention, those skilled in the art can easily design a corresponding detection reagent for detecting the above mutation, and whatever the detection reagent for detecting NF124 gene mutation is, the detection method is suitable, and it is within the scope of the present invention as long as it is used for early screening or diagnosis of retinal pigment degeneration diseases.
In a second aspect, embodiments of the present invention provide a screening reagent or a kit for early screening of retinitis pigmentosa disease, which contains a detection reagent for detecting a mutation of ZNF124 gene.
The early screening reagent or the kit provided by the invention can be used for early screening the retinal pigment degeneration disease before marriage or parturition by detecting the mutation of the ZNF124 gene, and is favorable for preventing the later generation from suffering the retinal pigment degeneration disease.
In alternative embodiments, the detection reagent detects a mutation in the ZNF124 gene comprising: c.219-1G-.
In alternative embodiments, the detection reagent is selected from any one or a combination of the following methods suitable for detecting a ZNF124 gene mutation: restriction fragment length polymorphism (PCR-RFLP), Denaturing Gradient Gel Electrophoresis (DGGE), allele specific PCR, DNA sequencing, DNA chip detection, Time of Flight Mass spectrometry (TOF), and single strand conformation polymorphism analysis (SSCP).
In alternative embodiments, the DNA sequencing method is a whole exon sequencing analysis or Sanger sequencing method.
In a third aspect, the embodiments of the present invention provide an auxiliary diagnostic reagent or kit for a retinal pigment degeneration disease, which contains a detection reagent for detecting a mutation of ZNF124 gene.
The auxiliary diagnostic reagent or the kit for the retinal pigment degeneration diseases, provided by the invention, can provide auxiliary basis or reference data for the diagnosis of the retinal pigment degeneration diseases by detecting the mutation of the ZNF124 gene, and provides guarantee for accurately diagnosing the retinal pigment degeneration diseases.
In alternative embodiments, the detection reagent detects a mutation in the ZNF124 gene comprising: c.219-1G-.
In alternative embodiments, the detection reagent is selected from any one or a combination of the following methods suitable for detecting a ZNF124 gene mutation: restriction fragment length polymorphism (PCR-RFLP), Denaturing Gradient Gel Electrophoresis (DGGE), allele specific PCR, DNA sequencing, DNA chip detection, Time of Flight Mass spectrometry (TOF), and single strand conformation polymorphism analysis (SSCP).
In alternative embodiments, the DNA sequencing method is a whole exon sequencing analysis or Sanger sequencing method.
In alternative embodiments, the type of sample detected by the reagent or kit is a body fluid, tissue, or hair from the subject to be tested.
In an optional embodiment, the subject to be measured is a human.
In an alternative embodiment, the body fluid is selected from blood, saliva or semen.
It should be noted that the types of samples detected by the reagent or the kit for screening or assisting diagnosis of retinal pigment degeneration diseases provided by the present invention include, but are not limited to, blood, saliva and semen, and other types of samples containing the subject DNA to be detected can also be used as detection samples of the reagent or the kit of the present invention.
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In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 shows the results of ophthalmologic examination of family probands of RP074 and their parents; in the figure: a, detecting the colored pigmentation of the retina of a patient by fundus oculi; and B, the macular OCT test reveals that the retinal nerve epithelial layer of the patient is thinned, the reflection of the inner and outer segment connecting layers of the photoreceptor disappears, and the pigment epithelial layer is atrophied.
FIG. 2 shows the results of the visual field and ERG detection of the family proband of RP 074; in the figure: A-B, visual field detection shows peripheral visual field loss, tubular visual field; c, ERG detection shows that the peaks of ERGa and b waves are greatly reduced under dark light, and the function of the photoreceptor cells of a patient is damaged.
FIG. 3 is an RP074 pedigree and ZNF124 gene mutation site; in the figure: WES analysis was performed on A, IV:4, IV:5, proband, IV:4, IV:5 and parents III:3, III: 4; b, exon sequencing analysis results reveal that parents III:3 and III:4 both carry ZNF124c.219-1G-heterozygous deletion mutation; c, Sanger sequencing verifies that IV:4 and IV:5 carry homozygous mutation, parents III:3 and III:4 both carry heterozygous deletion mutation, IV:6 is not diseased, and the deletion mutation is absent.
FIG. 4 is a RP131 pedigree and ZNF124 gene mutation site; in the figure: a, RP131 family map and family member genotype, and III:3 is proband; b, Sanger sequencing analysis shows that proband III:3 carries ZNF124c.219-1G > -homozygous deletion mutation; parents II:3, II:4 and sister III:4 are heterozygous carriers.
FIG. 5 shows the sequencing of the cDNA of the family Producer RP074 and the normal control cDNA, wherein 10 bases (red) of the cDNA of ZNF124 of Producer IV:4 are deleted.
FIG. 6 is a schematic representation of the mutation of ZNF124 gene; a, a ZNF124 gene deletion mutation site is positioned at a splice site of a No. 4 exon; b, the mutation causes the missplicing of mRNA to generate fragment deletion and base frame shift; c, the mutation finally causes the ZNF124 protein translation error.
FIG. 7 ZNF124 gene expression study; A-B, RT-PCR experiments of tissues of a mouse show that a homologous gene Gm20541 of ZNF124 in the mouse is widely expressed in tissues such as brain tissue, retina, liver, heart, muscle and the like; c, ZNF124 antibody can specifically recognize the ZNF124 protein which is transfected and expressed in 293T cells, and the size of the fragment is consistent with that of the fragment recognized by the tag protein Flag antibody; d, transfecting ZNF124 expression plasmids into 293T cells, and immunohistochemically staining ZNF124 and a tag Flag thereof respectively, wherein the result shows that ZNF124 protein is positioned in a cell nucleus; e, macaque retinal sections were stained with ZNF124 antibody, and ZNF124 protein was mainly localized in nuclei of opsonic, bipolar and ganglionic cells.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The features and properties of the present invention are described in further detail below with reference to examples.
Experimental example 1
Family analysis and ZNF124 mutation discovery
Among the collected RP families, the RP074 family is an autosomal recessive retinitis pigmentosa family in Han nationality in the southwest region of China, and 13 persons in 3 generations, and 2 persons in total suffer from RP. Clinical examination showed that patients with family proband of RP074, IV:4 and IV:5, had poor night vision from the age of 15, gradually progressed to night blindness, and impaired peripheral vision. Fundus examination revealed atrophy of optic nerve head, narrowing of retinal artery blood vessels, retinal pigmentation (a in fig. 1) in both eyes of the patient, and Optical Coherence Tomography (OCT) of the retina revealed thinning of the retinal nerve epithelium layer, with the most obvious outer nuclear layer in the patient; the reflection of the inner and outer section connecting layers of the photoreceptor disappears, and the sections are discontinuous; the pigment epithelial cell is partially lost and thinned, and the pigment epithelial layer is atrophied (B in figure 1), which is a typical pathological characterization of RP. Visual field examination revealed a peripheral visual field impairment in the patient (a, B in fig. 2). ERG examination suggested that the patient had photoreceptor cell function impaired (C in fig. 2).
The ZNF124 gene was found to have homozygous deletion mutations (NM-003431: exon5: c.219-1G >) co-segregating with the disease by whole exon sequencing analysis of the patient IV:4, IV:5 and their parents III:3 and III:4, respectively, of Shanghai Arbitrary Biotechnology Co., Ltd (A in FIG. 3). Analysis of homozygous regions in the genome also suggested the presence of homozygous regions at the ends of chromosome 1 (indicated by the B arrows in FIG. 3). Through Sanger sequencing verification of the DNA of the parents of the precursor IV:4 and the IV:5, the parents carry heterozygous mutation, the predecessor is homozygous mutation (C in figure 3), and the genotypes of the other members in the family are marked as A in figure 3, so that the genetic characteristics of the typical arRP are met.
Experimental example 2
Further data analysis of the collected whole exon sequencing RP samples in which no known gene mutation was detected revealed that another autosomal recessive RP family RP131 carries the ZNF124 mutation. RP131 is a Han family of RP in the northern region of China (A in FIG. 4). Probands carry the ZNF124 homozygous mutation (B in fig. 4), the parents of which are heterozygous carriers. The proband is a male patient, who is about 20 years old and shows night blindness and progressive visual field atrophy.
This mutation site was not detected in dbSNP database,1000 genes, NHLBI outer Sequencing Project (ESP), the ExAC Browser (Beta), gnomaD database, and was a rare mutation. The mutation was not detected in 3000 healthy control samples. This splicing mutation results in a coding region splice deletion after codon 73, resulting in a frame shift mutation; the mutated ZNF124 protein only retains the N-terminal KRAB-A box domain, and these data indicate that this ZNF24 mutation is a better RP candidate gene mutation. The detection of the gene mutation can be used for early screening or auxiliary diagnosis of the retinitis pigmentosa diseases.
Experimental example 3
To examine the effect of the deletion mutation (NM-003431: exon4: c.219-1G > -) on the transcription and translation of ZNF124 protein, the peripheral blood RNA of RP074 proband and parents thereof was extracted and reverse-transcribed into cDNA by the following method:
(a) separating peripheral blood leukocyte, placing in a 1.5ml centrifuge tube, adding 1ml Trizol extract, and standing at room temperature for 20 min;
(b) adding 200 mul chloroform, fully and uniformly mixing, and standing for 10 minutes at room temperature;
(c) placing the sample in a 4-degree centrifuge, centrifuging for 15 minutes at 10000 revolutions;
(d) carefully sucking the supernatant, adding isopropanol with the same volume, fully and uniformly mixing, centrifuging at 10000 rpm to precipitate RNA;
(e) washing the total RNA separated out by 75% ethanol, centrifuging, precipitating again, then airing and adding DEPC water for dissolving;
(f) the extracted total RNA was used to synthesize cDNA using a cDNA synthesis kit (Invitrogen, Waltham, MA, USA). Primers were designed based on the cDNA sequence of Gm 20541:
ZNF124-cDNA-F：5’-TGAGGATGTGGCTGTGAACT-3'；
ZNF124-cDNA-R：5’-ACTGGAACGACTGAAGGCTT-3'；
the cDNA segment of ZNF124 was subsequently sequenced by Sanger's method. The result shows that the cDNA of the ZNF124 of the patient has AGTTCATTTC total 10 base segment deletion after the mutation site and causes base frame shift after the deletion site (FIG. 5), which results in the coding error of the ZNF124 protein (FIG. 6).
Experimental example 4
ZNF124 tissue cell expression study
RT-PCR experiments of various tissues of mice show that ZNF124 is widely expressed in brain tissues, retinas, livers, hearts, muscles and the like of the mice by a homologous gene Gm20541 in the mice (A and B in figure 7). To further explore the cellular expression localization of ZNF124, we purchased polyclonal antibody to ZNF124(Proteintech) and transfected the constructed pCMV6-ZNF124-Flag expression plasmid into 293T cells using Lipofectamine 3000 transfection reagent (Thermo Fisher Scientific). Cell total protein is collected 48 hours after transfection and is subjected to immunoblotting detection, and the result shows that the antibody can specifically recognize ZNF124 protein expressed by 293T cells after transfection of pCMV6-ZNF124-Flag plasmid, and the position of the ZNF124 protein is consistent with that of a label antibody (C in FIG. 7), thereby proving that the antibody specificity is better. Transfection of ZNF124 expression plasmid into COS7 cells again, immunohistochemical staining of ZNF124 and its tag Flag, respectively, revealed that ZNF124 protein was localized to the nucleus (D in FIG. 7). Immunohistochemical staining experiments on macaque retina sections show that ZNF124 protein is positioned in the cell nucleus of retina photoreceptor cells, bipolar cells and ganglion cells (E in FIG. 7), and is suggested to be used as a transcription factor for regulating the expression of other genes.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. 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 (12)
1. The application of a detection reagent for detecting ZNF124 gene mutation in preparing a reagent or a kit for early screening or auxiliary diagnosis of retinitis pigmentosa diseases is characterized in that the detection reagent for detecting the ZNF124 gene mutation comprises the following steps: c.219-1G > -;
wherein, the mRNA transcript number of the ZNF124 gene is NM-003431;
the mutation c.219-1G > -means: compared with the ZNF124 gene of a normal individual, the ZNF124 gene of the individual suffering from the retinitis pigmentosa diseases has G deletion at the 1 st position upstream of the 219 th base of the coding region.
2. The use as claimed in claim 1 wherein the detection reagent is selected from any one or a combination of the following methods for detecting a mutation in the ZNF124 gene: restriction fragment length polymorphism, denaturing gradient gel electrophoresis, allele specific PCR, DNA sequencing, DNA chip detection, time-of-flight mass spectrometry, and single strand conformation polymorphism analysis.
3. Use according to claim 2, wherein the DNA sequencing method is whole exon sequencing or Sanger sequencing.
4. An early screening reagent or a kit for retinitis pigmentosa diseases, which is characterized by comprising a detection reagent for detecting mutation of ZNF124 gene; the detection reagent for detecting the mutation of ZNF124 gene comprises: c.219-1G > -;
wherein, the mRNA transcript number of the ZNF124 gene is NM-003431;
the mutation c.219-1G > -means: compared with the ZNF124 gene of a normal individual, the ZNF124 gene of the individual suffering from the retinitis pigmentosa diseases has G deletion at the 1 st position upstream of the 219 th base of the coding region.
5. The reagent or kit as claimed in claim 4, wherein the detection reagent is selected from any one or combination of the following methods suitable for detecting ZNF124 gene mutation: restriction fragment length polymorphism, denaturing gradient gel electrophoresis, allele specific PCR, DNA sequencing, DNA chip detection, time-of-flight mass spectrometry, and single strand conformation polymorphism analysis.
6. The reagent or kit according to claim 5, wherein the DNA sequencing method is whole exon sequencing or Sanger sequencing.
7. An auxiliary diagnostic reagent or a kit for retinitis pigmentosa diseases, which contains a detection reagent for detecting mutation of ZNF124 gene; the detection reagent for detecting the mutation of ZNF124 gene comprises: c.219-1G > -;
wherein, the mRNA transcript number of the ZNF124 gene is NM-003431;
the mutation c.219-1G > -means: compared with the ZNF124 gene of a normal individual, the ZNF124 gene of the individual suffering from the retinitis pigmentosa diseases has G deletion at the 1 st position upstream of the 219 th base of the coding region.
8. The reagent or kit as claimed in claim 7, wherein the detection reagent is selected from any one or combination of the following methods suitable for detecting ZNF124 gene mutation: restriction fragment length polymorphism, denaturing gradient gel electrophoresis, allele specific PCR, DNA sequencing, DNA chip detection, time-of-flight mass spectrometry, and single strand conformation polymorphism analysis.
9. The reagent or kit according to claim 8, wherein the DNA sequencing method is whole exon sequencing analysis or Sanger sequencing.
10. The reagent or kit according to any one of claims 4 to 9, wherein the type of sample detected by the reagent or kit is a body fluid, tissue or hair from a subject to be tested.
11. The reagent or the kit according to claim 10, wherein the subject to be tested is a human.
12. A reagent or kit according to claim 11, wherein the body fluid is selected from blood, saliva or semen.
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| CN202010114890.4A CN111304314B (en) | 2020-02-25 | 2020-02-25 | Application of ZNF124 gene in early screening or auxiliary diagnosis of retinitis pigmentosa diseases |
| US17/416,869 US20220049310A1 (en) | 2020-02-25 | 2020-10-20 | Use of ZNF124 Gene in Early Screening or Auxiliary Diagnosis of Retinitis Pigmentosa Disease |
| PCT/CN2020/122230 WO2021169333A1 (en) | 2020-02-25 | 2020-10-20 | Use of znf124 gene in early screening or auxiliary diagnosis of retinitis pigmentosa diseases |
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| CN111778281B (en) * | 2020-07-17 | 2021-04-23 | 四川省人民医院 | Construction method and application of retina bipolar cytopathy model |
| CN117487816B (en) * | 2023-11-03 | 2024-06-04 | 中山大学孙逸仙纪念医院 | Application of ZNF709 gene in preparing medicament for treating PBC |
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