CN110872613A - 用于诊断阿维利诺角膜营养不良的引物 - Google Patents
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Abstract
本发明涉及用于诊断阿维利诺角膜营养不良的实时PCR引物对和探针,更特别地涉及这种用于诊断阿维利诺角膜营养不良的实时PCR引物对和探针,其能够准确地诊断BIGH3基因外显子4中突变的存在或不存在,所述突变是阿维利诺角膜营养不良的原因。使用根据本发明的引物对和探针可以比使用DNA芯片或PCR的传统方法更快速并准确的模式诊断阿维利诺角膜营养不良。
Description
本申请是基于申请日为2009年12月1日,优先权日为2009年4月17 日,申请号为201510121642.1,发明名称为:“用于诊断阿维利诺角膜营养 不良的引物”的专利申请的分案申请。
技术领域
本发明涉及用于诊断阿维利诺角膜营养不良(Avellino corneal dystrophy) 的实时PCR引物对和探针,更特别地涉及这种用于诊断阿维利诺角膜营养 不良的实时PCR引物对和探针,其能够准确地诊断BIGH3基因外显子4中 是否存在突变,所述突变是阿维利诺角膜营养不良的原因。
技术背景
角膜营养不良是常染色体显性遗传疾病,其开始在角膜中间具有模糊 症状且逐渐蔓延,最终患者到老年时丧失视力。角膜营养不良包括阿维利 诺角膜营养不良、颗粒状角膜营养不良、格子状I型角膜营养不良、里斯- 布克乐斯(Reis-bucklers)角膜营养不良等,且由编码白βIG-H3蛋白的基因 突变引起。
患有阿维利诺角膜营养不良的杂合子患者随着年龄增长似乎出现严重 的视力丧失,而纯合子患者从6岁开始似乎完全丧失视力。阿维利诺角膜 营养不良是1988年新命名的疾病,从通常称为颗粒状角膜营养不良中划 分出来,因为发现它具有分离的症状和遗传基础。同样地,己知它是世界 范围内最常见的角膜营养不良,基于遗传分析的韩国1/340至1/1000的患 病率(杂合子的情况)表明它是常见的营养不良(Holland,E.J.等,Ophthalmology,99:1564,1992;Kennedy,S.M.等,Br.J.Ophthalmol.,80:489, 1996;Dolmetsch,A.M.等,Can.J.Ophthalmol 31:29,1996;Afshari,N.A. 等,Arch.Ophthalmol,119:16,2001;Stewart,H.S.Hum.Mutat.,14:126, 1999)。
本发明人发现,如果患有杂合阿维利诺角膜营养不良的患者进行准分 子激光原位角膜磨削术(LASIK),两年后,角膜的浑浊度开始明显扩大且最 终引起视力丧失(Jun,R.M.等,Opthalmology,111:463,2004)。以前,进行 眼科手术期望通过准分子激光原位角膜磨削术或准分子激光手术将使患有 角膜营养不良的患者摆脱视力模糊。同样地,即使在韩国,大约己进行30 万例准分子激光原位角膜磨削术,其中基于1/1000的患有阿维利诺角膜营 养不良的杂合子患者的最低估计,假定有300人丧失视力。经历准分子激 光原位角膜磨削术的患者主要在其20岁及30岁进行生产活动。因此,他 们的视力丧失导致严重的社会问题和经济问题。
此外,美国2000年批准准分子激光原位角膜磨削术后,己发现经历 准分子激光原位角膜磨削术的患有阿维利诺角膜营养不良的非洲裔美国患 者丧失视力,其推断许多相似的病例可发生在世界各地。
因此,尽管为了通过准分子激光原位角膜磨削术预防阿维利诺角膜营 养不良的进展,需要准确地诊断阿维利诺角膜营养不良,但仅通过角膜浑 浊度的显微观察进行诊断阿维利诺角膜营养不良,因此医生经常遗漏进行 准分子激光原位角膜磨削术的患者的潜在症状,其导致视力丧失。因此, 快速并准确地诊断角膜营养不良是迫切需要的。
己研发了用于检测BIGH3基因突变的DNA芯片,所述突变是阿维 利诺角膜营养不良的原因(韩国专利早期公开号10-2007-0076532)。然而, 使用所述DNA芯片诊断阿维利诺角膜营养不良不利地需要几个步骤,包括 样品中扩增DNA的步骤、使扩增的DNA与DNA芯片杂交的步骤、清洗杂 交的DNA芯片的步骤和检测阳性反应的步骤。
因此,本发明人己进行大量努力以研发能够更有效地诊断阿维利诺角 膜营养不良的方法,结果,己发现,如果使用具有序列号1-2核苷酸序列的 引物及具有序列号13-14核苷酸序列的探针通过实时PCR方法诊断阿维利 诺角膜营养不良,可以比传统方法更快速并准确的方式诊断阿维利诺角膜 营养不良,从而完成本发明。
发明内容
本发明的主要目的在于使用实时PCR方法提供用于更有效并准确地 诊断阿维利诺角膜营养不良的引物对和探针。
为了实现上述目的,本发明提供用于诊断阿维利诺角膜营养不良的实 时PCR引物对,其由选自由下列核苷酸序列组成的组的核苷酸序列表示: 序列号1-2、序列号3-4、序列号5-6、序列号7-8、序列号9-10、序列号11-12、 序列号13-14、序列号15-16、序列号17-18、序列号19-20、序列号21-22 及序列号23-24。
本发明还提供了用于诊断阿维利诺角膜营养不良的实时PCR探针,其 由选自由序列号25-42组成的核苷酸序列表示。
本发明包括以下内容:
项1.一种用于诊断阿维利诺角膜营养不良的实时PCR引物对,其由 选自由下列核苷酸序列组成的组的核苷酸序列表示:序列号1-2、序列号3-4、 序列号5-6、序列号7-8、序列号9-10、序列号11-12、序列号13-14、序列 号15-16、序列号17-18、序列号19-20、序列号21-22及序列号23-24;
项2.一种用于诊断阿维利诺角膜营养不良的实时PCR探针,其由选 自由序列号25-42组成的组中的核苷酸序列表示;
项3.根据项2所述的用于诊断阿维利诺角膜营养不良的实时PCR探 针,其中所述实时PCR探针用VIC或FAM标记。
附图说明
图1示出了设计实时PCR引物和探针获得的结果。在图1中,“A” 示出了使用最佳引物和探针进行的实时PCR的结果,“B”和“C”示出了 使用不同于“A”中的引物进行的实时PCR的结果。
图2示出了为了检测引起阿维利诺角膜营养不良的基因突变,使用根 据本发明的实时PCR引物进行的实时PCR的结果。
具体实施方式
一方面,本发明针对用于诊断阿维利诺角膜营养不良的实时PCR引物 对,其由选自由下列核苷酸序列组成的组的核苷酸序列表示:序列号1-2、 序列号3-4、序列号5-6、序列号7-8、序列号9-10、序列号11-12、序列号 13-14、序列号15-16、序列号17-18、序列号19-20、序列号21-22及序列号 23-24。
阿维利诺角膜营养不良是由遗传异常引起的疾病,其中BIGH3基因外 显子4中的序列CGC突变为CAC从而使位于BIGH3蛋白残基的精氨酸突 变为组氨酸(R124H)。
当使用本发明的引物实施实时PCR方法时,可以比使用DNA芯片的 传统方法更快速并准确的方式诊断阿维利诺角膜营养不良。
在实时PCR方法中,很难确定温度条件,因为应在相同的温度条件下 进行使用引物和探针的实验。特别是,如果只检测一个似阿维利诺角膜营 养不良的突变位置,应该在能够使引物和探针结合的温度条件下使用它们。 同样地,探针在一定状态下在非常有限的温度范围1℃至3℃的温度下能够 结合,在所述状态下检测正常基因的探针和检测突变基因的探针只有一个 核苷酸不同。
由于这些条件,重要的是找到探针和引物能与目的基因结合的相同温 度。特别地,重要的是设计突变探针和正常探针以使其温度在有限范围内 可尽量不同。换言之,引物和探针的温度应该相互一致,正向引物和反向 引物的温度条件应该相互一致,且突变探针和正常探针之间的温度差异应 能够最大化。图1A示出了使用精心设计的引物和探针的结果,
图1B和1C示出了使用不同于图1A的引物而使用与图1A相同的探针 的结果。可以看出,引物和探针的设计对于读数有显著影响。
在本发明中,为了构建使用实时PCR方法诊断阿维利诺角膜营养不良 的最佳引物,设计了序列号1-2、序列号3-4、序列号5-6、序列号7-8、序 列号9-10、序列号11-12、序列号13-14、序列号15-16、序列号17-18、序 列号19-20、序列号21-22及序列号23-24引物对,且使用每组设计的引物 对进行实时PCR。结果,发现使用序列号1-2引物对示出了最佳结果。
另一方面,本发明针对用于诊断阿维利诺角膜营养不良的实时PCR探 针,其由选自序列号25-42组成的核苷酸序列表示。
在本发明中,为了构建使用实时PCR方法诊断阿维利诺角膜营养不良 的最佳探针,设计了序列号25-42的引物,且使用每组设计的引物进行实时 PCR。结果,发现使用探针序列号13-14示出了最佳结果。
实施例
在下文中,将参考实施例进一步详细描述本发明。对于本领域普通技术人员显而易见的是,这些实施例只是说明性目的,而不应限制本发明的 范围。即,以下步骤只描述为说明性步骤且不限制本发明的范围。
实施例1:构建实时PCR引物和MGB探针
为了构建能够扩增包含BIGH3基因外显子4突变区的引物,使用Primer Express3.0软件(Applied Biosystems U.S.A)设计了序列号1-2、序列号3-4、 序列号5-6、序列号7-8、序列号9-10、序列号11-12、序列号13-14、序列 号15-16、序列号17-18、序列号19-20、序列号21-22及序列号23-24引物 对。
ACD Fw引物:5'-TCC ACC ACC ACT CAG CTG TA(序列号1)
ACD Re引物:5'-CCA TCT CAG GCC TCA GCT T(序列号2)(60bp)
AV Fw引物:5'-TGC AGC CCT ACC ACT CTC AA(序列号3)
AV Re引物:5'-AGG CCT CGT TGC TAG G(序列号4)(150bp)
实时Fw引物(Real Fw primer):5'-TAG TCT CTT ATT CTA ATA GA(序 列号5)
实时Re引物(Real Re primer):5'-GCT GCA GAC TCT GTG TTT AA(序 列号6)(860bp)
ACD Fw2引物:5'-CCA TCC CTC CTT CTG TCT TCT G(序列号7)
ACD Re2引物:5'-CGG GCC CCT CCA TCT C(序列号8)(140bp)
ACD Fw3引物:5'-CAG AGA AGG GAG GGT GTG GTT(序列号9)
ACD Re3引物:5'-GGG CGA AGA TGG TGA AGC T(序列号10)(190bp)
ACD Fw4引物:5'-TCC TCG TCC TCT CCA CCT GTA(序列号11)
ACD Re4引物:5'-AGC TGG CAA GGA GGC CC(序列号12)
ACD Fw5引物:5'-TTT GGG CTT TCC CAC ATG C(序列号13)
ACD Re5引物:5'-GGC AGA CGG AGG TCA TCT CA(序列号14)
ACD Fw6引物:5'-GTAGTACCG TGC TCT CTG(序列号15)
ACD Re6引物:5'-AGT TCC CCA TAA GAA TCC CCC(序列号16)
ACD Fw7引物:5'-GGC TGG ACC CCC AGA GG(序列号17)
ACD Re7引物:5'-ACC CCT CGG GGA AGT AAG G(序列号18)
ACD Fw8引物:5'-AAC CTT TAC GAG ACC CTG GGA(序列号19)
ACD Re8引物:5'-GAC TCC CAT CCA TCA TGC CC(序列号2 0)
ACD Fw9的引物:5'-AGT CGT TGG ATC CAC CAC CA(序列号21)
ACD Re9引物:5'-GAC GTC ATT TCC TAC TGT TTC AGG(序列号22)
ACD Fw10引物:5'-CCC CCC AGA AAC AGC CTG(序列号23)
ACD Re10引物:5'-TTC TAA GGG GTT AAG GAG AAA GCT T(序列号 24)
为了检测BIGH3基因外显子4中的鸟嘌呤至腺嘌呤的突变,构建了序 列号25-42的探针。
用VIC标记与无突变的正常基因片段结合的探针,并用FAM标记与 具有突变的基因片段结合的探针,且小沟结合子(MGB)与探针结合以促进与 互补基因片段的结合。
正常探针1:VIC-CAC GGA CCGCAC GGA-NFQ(序列号25)(15bp)
突变探针1:FAM-CAC GGA CCACAC GGA-NFQ(序列号26)
正常探针2:VIC-ACA CGG ACCGCA CG-NFQ(序列号27)
突变探针2:FAM-ACA CGG ACCACA CG-NFQ(序列号28)(14bp)
正常探针3:VIC-TAC ACG GAC CGC A-NFQ(序列号29)
突变探针3:FAM-TAC ACG GAC CAC A-NFQ(序列号30)(13bp)
正常探针4:VIC-CTG TAC ACG GAC CGC ACG-NFQ(序列号31)
突变探针4:FAM-CTG TAC ACG GAC CAC ACG-NFQ(序列号32) (18bp)
正常探针5:VIC-CTG TAC ACG GAC CGC ACG GAG-NFQ(序列号33) 突变探针5:FAM-CTG TAC ACG GAC CAC ACG GAG-NFQ(序列号 34)(21bp)
正常探针6:VIC-GCT GTA CAC GGA CCGCAC GGA GAA-NFQ(序列 号35)
突变探针6:FAM-GCT GTA CAC GGA CCACAC GGA GAA-NFQ(序列 号36)
正常探针7:VIC-ACC GCA CGG AGA AGC-NFQ(序列号37)
突变探针7:FAM-ACC ACA CGG AGA AGC-NFQ(序列号38)
正常探针8:VIC-ACC GCA CGG AGA AGC TGA GGC-NFQ(序列号39) 突变探针8:FAM-ACC ACA CGG AGA AGC TGA GGC-NFQ(序列号 40)
正常探针8:VIC-ACC GCA CGG AGA AGC TGA GGC CTG-NFQ(序列 号41)
突变探针8:FAM-ACC ACA CGG AGA AGC TGA GGC CTG-NFQ(序 列号42)
实施例2:使用实时PCR诊断阿维利诺角膜营养不良
样品取自试验者的血液、毛根和口腔上皮细胞,并从样品中分离DNA。 使用部分修正的酚/氯仿抽提方法进行DNA的分离与纯化(Miller,SA等, Nucl.Acids Res.16:1215,1988),并将分离的DNA溶解于适量的TE缓冲液 中(10mM Tris-Cl,1mM EDTA,pH7.4),通过1%琼脂糖凝胶电泳确定并用 作PCR中的模板DNA。
使用用于扩增含有突变区的片段的引物(序列号1-12)和实施例1中构 建的探针(序列号13-24)进行PCR反应。
制备含有10pmol每种引物和5pmol每种探针的25μl样品混合物并用 于PCR反应中。
在以下条件下进行实时PCR反应:36个循环,每个循环包含95℃下 反应10分钟、92℃下反应15秒及60℃下反应1分钟,之后在60℃下反应 5分钟。
每个循环后,测定荧光。将对VIC染料阳性的样品诊断为具有正常基 因,将对FAM基因阳性的样品诊断为具有突变基因。
结果,可以看出,使用引物对序列号1-2与探针序列号25-26示出了最 准确及有效的结果(图2)。
虽然己参考具体特征详细描述本发明,但对于本领域技术人员显而易 见的是,这些描述只是优选实施方案并不限制本发明的范围。因此,本发 明的主要范围将通过附属权利要求及其等价物确定。
工业应用性
使用根据本发明的引物对和探针可以比使用DNA芯片或PCR的传统 方法更快速并准确的模式诊断阿维利诺角膜营养不良。
序列目录自由正文
附加电子文件。
序列表
<110> 阿维利诺株式会社
<120> 用于诊断阿维利诺角膜营养不良的引物
<130> FP11KR1362
<140> PCT/KR2009/007099
<141> 2009-12-01
<150> 10-2009-0033528
<151> 2009-04-17
<160> 42
<170> PatentIn version 3. 2
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<211> 19
<212> DNA
<213> 人工
<220>
<223> 引物
<400> 1
ccaccaccac tcagctgta 19
<210> 2
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<212> DNA
<213> 人工
<220>
<223> 引物
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ccatctcagg cctcagctt 19
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<220>
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<220>
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<400> 5
tagtctctta ttctaataga 20
<210> 6
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<212> DNA
<213> 人工
<220>
<223> 引物
<400> 6
gctgcagact ctgtgtttaa 20
<210> 7
<211> 22
<212> DNA
<213> 人工
<220>
<223> 引物
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ccatccctcc ttctgtcttc tg 22
<210> 8
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<212> DNA
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<220>
<223> 引物
<400> 8
cgggcccctc catctc 16
<210> 9
<211> 21
<212> DNA
<213> 人工
<220>
<223> 引物
<400> 9
cagagaaggg agggtgtggt t 21
<210> 10
<211> 19
<212> DNA
<213> 人工
<220>
<223> 引物
<400> 10
gggcgaagat ggtgaagct 19
<210> 11
<211> 21
<212> DNA
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<220>
<223> 引物
<400> 11
tcctcgtcct ctccacctgt a 21
<210> 12
<211> 17
<212> DNA
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<220>
<223> 引物
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agctggcaag gaggccc
<210> 13
<211> 19
<212> DNA
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<220>
<223> 引物
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tttgggcttt cccacatgc 19
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gtagtaccgt gctctctg 18
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ggctggaccc ccagagg 17
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acccctcggg gaagtaagg19
<210> 19
<211> 21
<212> DNA
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<223> 引物
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aacctttacg agaccctggg a 21
<210> 20
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<220>
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<400> 20
gactcccatc catcatgccc 20
<210> 21
<211> 20
<212> DNA
<213> 人工
<220>
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<400> 21
agtcgttgga tccaccacca 20
<210> 22
<211> 24
<212> DNA
<213> 人工
<220>
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<400> 22
gacgtcattt cctactgttt cagg24
<210> 23
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<400> 23
ccccccagaa acagcctg 18
<210> 24
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<220>
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ttctaagggg ttaaggagaa agctt25
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<212> DNA
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<220>
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<210> 29
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<212> DNA
<213> 人工
<220>
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tacacggacc gca 13
<210> 30
<211> 13
<212> DNA
<213> 人工
<220>
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tacacggacc aca 13
<210> 31
<211> 18
<212> DNA
<213> 人工
<220>
<223> 探针
<400> 31
ctgtacacgg accgcacg 18
<210> 32
<211> 18
<212> DNA
<213> 人工
<220>
<223> 探针
<400> 32
ctgtacacgg accacacg18
<210> 33
<211> 21
<212> DNA
<213> 人工
<220>
<223> 探针
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ctgtacacgg accgcacgga g 21
<210> 34
<211> 21
<212> DNA
<213> 人工
<220>
<223> 探针
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ctgtacacgg accacacgga g 21
<210> 35
<211> 24
<212> DNA
<213> 人工
<220>
<223> 探针
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gctgtacacg gaccgcacgg agaa24
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<211> 24
<212> DNA
<213> 人工
<220>
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gctgtacacg gaccacacgg agaa 24
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<212> DNA
<213> 人工
<220>
<223> 探针
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<211> 15
<212> DNA
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<223> 探针
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<211> 21
<212> DNA
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<220>
<223> 探针
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accgcacgga gaagctgagg c 21
<210> 40
<211> 21
<212> DNA
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<220>
<223> 探针
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accacacgga gaagctgagg c 21
<210> 41
<211> 24
<212> DNA
<213> 人工
<220>
<223> 探针
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accgcacgga gaagctgagg cctg24
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<211> 24
<212> DNA
<213> 人工
<220>
<223> 探针
<400> 42
accacacgga gaagctgagg cctg 24
Claims (3)
1.一种用于诊断阿维利诺角膜营养不良的实时PCR引物对,其由选自由下列核苷酸序列组成的组的核苷酸序列表示:序列号1-2、序列号3-4、序列号5-6、序列号7-8、序列号9-10、序列号11-12、序列号13-14、序列号15-16、序列号17-18、序列号19-20、序列号21-22及序列号23-24。
2.一种用于诊断阿维利诺角膜营养不良的实时PCR探针,其由选自由序列号25-42组成的组中的核苷酸序列表示。
3.根据权利要求2所述的用于诊断阿维利诺角膜营养不良的实时PCR探针,其中所述实时PCR探针用VIC或FAM标记。
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CA2759222A1 (en) | 2010-10-21 |
RU2011146553A (ru) | 2013-05-27 |
US20120077200A1 (en) | 2012-03-29 |
CN102459593A (zh) | 2012-05-16 |
US11268146B2 (en) | 2022-03-08 |
SG175732A1 (en) | 2011-12-29 |
BRPI0924016A2 (pt) | 2016-10-11 |
ZA201107967B (en) | 2013-08-28 |
RU2534817C2 (ru) | 2014-12-10 |
EP2420574B1 (en) | 2014-10-29 |
KR20100115030A (ko) | 2010-10-27 |
WO2010120027A1 (ko) | 2010-10-21 |
JP2012523831A (ja) | 2012-10-11 |
CN104774930A (zh) | 2015-07-15 |
US20180274034A1 (en) | 2018-09-27 |
KR101251538B1 (ko) | 2013-04-08 |
US20220205044A1 (en) | 2022-06-30 |
US9938581B2 (en) | 2018-04-10 |
AU2009344501A1 (en) | 2011-11-17 |
EP2420574A4 (en) | 2012-08-29 |
EP2420574A1 (en) | 2012-02-22 |
JP5738842B2 (ja) | 2015-06-24 |
IL215845A0 (en) | 2012-01-31 |
EP2848689A1 (en) | 2015-03-18 |
US20150093751A1 (en) | 2015-04-02 |
CN102459593B (zh) | 2015-04-08 |
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