视网膜色素变性合并肢端病变一家系致病基因筛查
摘要
[目的]
应用候选基因筛查、连锁分析方法对一合并有肢端病变的视网膜色素变性家系进行致病基因排除定位。
[材料和方法]
1.通过家系调查收集家系临床资料。
2.抽取家系成员外周血并提取全血基因组DNA。
3.查阅文献及网络数据库,确定已知的发病率高的视网膜色素变性致病基因为候选基因。
4.对于候选基囚USH2A.RPGR,通过选取微卫星标记,对已知遗传状态的家系成员行聚丙烯酰胺凝胶电泳,银染显色后进行非参数连锁分析。
5.对于候选基因RHO、PRPF3、PRPF8、PRPF31、RDS、RP10、RPGR、RP1基因的突变热点区域设计引物,将先证者基因组DNA进行PCR扩增后直接测序,通过与网络数据库进行比对,明确有无突变。
[结果]
家系临床研究表明,YPH家系所患视网膜色素变性系遗传性疾病,常染色体显性遗传可能性大。对于USH2A、RPGR做的家系非参连锁分析结果显示,家系中患者与标记位点无连锁不平衡现象,故可排除这两个基因致病。对先证者的RHO、 PRPF3、PRPF8、PRPF31、RDS、RP10、RPGR基因编码区或突变热点区域直接测序结果显示,未发现致病性突变。
先证者RP1基因编码区有一杂合性突变导致RP1蛋白D998Y突变,经过生物信息学方法预测,这一突变是致病性突变。但是,对家系其他成员的筛查却发现这一突变不与家系中患者共分离,故很可能不是YPH家系的致病性突变。
[结论]
家系中RP1蛋白D998Y突变的意义尚待进一步评估。
YPH家系致病基因可能不是已知常见的视网膜色素变性致病基因。
Objective
To detect the mutation in a family with retinitis pigmentosa and acropathy, using candidate genes screening.
Materials and Methods
1. Clinical data were collected in this family. All family members were studied with medical history, ophthalmologic examinations, ERG, VEP and whole body physical examinations.
2. Venous blood was collected from research subjects and genomic DNA was extracted.
3. Candidate genes were determined by reviewing literature and online databases.
4. To screen the genes USH2A and RPGR, linkage analysis were performed after detecting the microsatellite markers of this family.
5. To screen the genes RHO, PRPF3, PRPF8, PRPF31, RP1, RDS, RP10and RPGR, primers were designed and direct sequencing were performed after PCR. Then results were compared with web databases.
Results
Patients in this family manifest retinal degeneration with acropathy, which represent a novel retinitis pigmentosa syndrome. The inheritance pattern is not clear, we consider autosomal dominant most possible. The screening of RHO, PRPF3, PRPF8, PRPF31, RDS, RP10and RPGR genes in the proband of YPH family were negative.
We found a novel mutation in RP1gene (D998Y) in the proband. D998Y is thought to be pathologic by bioinformatic evaluation, but it does not cosegregate with the patients in this family. Further evaluation is needed to determine this mutation.
Conclusion
Whether RP1D998Y mutation is the disease-causing mutation in YPH family should be further evaluated.
We consider a novel disease-causing mutation may exist in YPH family.
应用候选基因筛查、连锁分析方法对一合并有肢端病变的视网膜色素变性家系进行致病基因排除定位。
[材料和方法]
1.通过家系调查收集家系临床资料。
2.抽取家系成员外周血并提取全血基因组DNA。
3.查阅文献及网络数据库,确定已知的发病率高的视网膜色素变性致病基因为候选基因。
4.对于候选基囚USH2A.RPGR,通过选取微卫星标记,对已知遗传状态的家系成员行聚丙烯酰胺凝胶电泳,银染显色后进行非参数连锁分析。
5.对于候选基因RHO、PRPF3、PRPF8、PRPF31、RDS、RP10、RPGR、RP1基因的突变热点区域设计引物,将先证者基因组DNA进行PCR扩增后直接测序,通过与网络数据库进行比对,明确有无突变。
[结果]
家系临床研究表明,YPH家系所患视网膜色素变性系遗传性疾病,常染色体显性遗传可能性大。对于USH2A、RPGR做的家系非参连锁分析结果显示,家系中患者与标记位点无连锁不平衡现象,故可排除这两个基因致病。对先证者的RHO、 PRPF3、PRPF8、PRPF31、RDS、RP10、RPGR基因编码区或突变热点区域直接测序结果显示,未发现致病性突变。
先证者RP1基因编码区有一杂合性突变导致RP1蛋白D998Y突变,经过生物信息学方法预测,这一突变是致病性突变。但是,对家系其他成员的筛查却发现这一突变不与家系中患者共分离,故很可能不是YPH家系的致病性突变。
[结论]
家系中RP1蛋白D998Y突变的意义尚待进一步评估。
YPH家系致病基因可能不是已知常见的视网膜色素变性致病基因。
Objective
To detect the mutation in a family with retinitis pigmentosa and acropathy, using candidate genes screening.
Materials and Methods
1. Clinical data were collected in this family. All family members were studied with medical history, ophthalmologic examinations, ERG, VEP and whole body physical examinations.
2. Venous blood was collected from research subjects and genomic DNA was extracted.
3. Candidate genes were determined by reviewing literature and online databases.
4. To screen the genes USH2A and RPGR, linkage analysis were performed after detecting the microsatellite markers of this family.
5. To screen the genes RHO, PRPF3, PRPF8, PRPF31, RP1, RDS, RP10and RPGR, primers were designed and direct sequencing were performed after PCR. Then results were compared with web databases.
Results
Patients in this family manifest retinal degeneration with acropathy, which represent a novel retinitis pigmentosa syndrome. The inheritance pattern is not clear, we consider autosomal dominant most possible. The screening of RHO, PRPF3, PRPF8, PRPF31, RDS, RP10and RPGR genes in the proband of YPH family were negative.
We found a novel mutation in RP1gene (D998Y) in the proband. D998Y is thought to be pathologic by bioinformatic evaluation, but it does not cosegregate with the patients in this family. Further evaluation is needed to determine this mutation.
Conclusion
Whether RP1D998Y mutation is the disease-causing mutation in YPH family should be further evaluated.
We consider a novel disease-causing mutation may exist in YPH family.
引文
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