一中国白族常染色体显性遗传视网膜色素变性家系基因定位研究
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摘要
背景
视网膜色素变性(retinitis pigmentosa, RP)是视网膜变性中最常见的一组以进行性光感受器细胞及视网膜色素上皮功能丧失为共同表现的致盲性眼病,其具有高度的遗传和表型异质性。根据RP遗传方式的不同,可将其分为常染色体显性遗传RP (autosomal dominant RP, adRP)、常染色体隐性遗传RP(autosomal recessive RP, arRP)和X伴性连锁遗传RP (X-lined RP, XLRP),少数表现为双基因突变遗传及线粒体遗传。当因缺乏家族史而无法确定其遗传方式时,则为散发型RP (sporadic RR,SRP),大多数SRP表现为arRP。经统计,引起adRP、arRP、XLRP的突变基因分别有20、26、2种。RP是发达国家工作年龄中致盲的最普遍原因,全球RP的发病率约为1／3500,已超过100万人受累,但目前尚无有效的预防和治疗措施,而对RP致病基因的确立则可为探讨RP发病机制,进行遗传咨询、产前诊断及基因治疗创造条件。研究表明,与人类光感受器功能障碍或变性有关的基因座约有70多个,目前已发现53个基因座与RP有关,因此对RP致病基因的定位研究仍然是分子遗传学研究的热点。
adRP是最常见的RP遗传方式,目前在已报道的53个基因座中,已确定19个与adRP有关,其中RHO、PRPF31、RP1、IMPDH1及RDS基因是引起adRP常见的突变基因。RHO与PRPF31基因是我国汉族RP人群中最常见的突变基因,但在白族人群中尚未见报道。至今,RHO基因已超过120种不同类型的突变被发现,在这些突变中,90%为单个碱基置换的点突变,一般突变范围不超过20个碱基对。研究发现,该基因突变存在种族差异,在欧美、日本、中国其突变所占adRP分别为25%、5.9%、7.7%,南美人群中最常见的RHO基因突变类型是Pro23His,而亚洲,所有已报道的RHO基因突变均集中在羧基末端(QVSPA), Pro347Lue是该区域中最多见的突变热点,也是全球性的多发突变位点。PRPF31基因是仅次于RHO基因座的常见adRP基因,其最先是在一个英国adRP大家族通过连锁分析发现并将其定位在染色体19q13.4, PRPF31基因突变包括错义突变、缺失、插入及剪接位点的改变,目前已有30个不同位点的突变被发现,其较多见的突变位点位于外显子5、外显子6、外显子7、外显子8、外显子11及内含子与外显子交界处。据统计,在美国等西方国家RP1突变是较常见的,占所有RP的7%,其中以位于外显子4的错义突变(R677X)多见,在我国,其突变较少见。RDS突变可引起很多类型的视网膜变性,目前已发现超过70个RDS基因突变与adRP和常染色体显性黄斑变性(adMD)有关,其中引起adRP的突变位点仅占5%。RDS突变所致的adRP有地区差异,在美国及北欧较多见,在我国等亚洲国家较少见,RDS基因突变多位于外显子1。IMPDH1基因突变多见于外显子7,目前国内外对IMPDH1基因的突变报道尚不多,但其突变所致的adRP发病早,且严重。
在这些已发现的RP基因座中大多数是通过家系连锁分析的方法定位的,连锁分析是一种成熟的基因定位克隆技术,90年代初Inglehearn、Greenberg等就利用短串联重复序列(short tandem repeat,STR)遗传标记进行连锁分析,分别在染色体7p、17P上发现了新的adRP致病基因,随后也相继有报道。该技术是其以二代或二代以上的家系材料为基础,利用人类基因组中存在的遗传标记进行分析,观察标记位点与疾病致病基因位点在家系内是否呈共分离,并计算出遗传距离及连锁程度,从而确定致病的候选基因。
遗传病具有一定的家族遗传倾向,利用家系对遗传性疾病的研究是基因定位的一大特色,也是发挥我国人口资源优势的一大特色。RP致病基因的突变是多种多样的,特别是在不同地区、不同民族中,不同基因的突变可导致RP,相同基因的不同突变也可引起RP。白族是我国西南地区一个不同于汉族的少数民族,其世代迁移少,是相对封闭的种族,具有良好的单基因疾病遗传背景,对其致病基因的定位研究,将丰富我国RP基因的突变图谱,为创建我国RP人群遗传图谱及基因序列结构功能信息系统提供更多信息。
研究目的
确定该白族adRP家系的发病与RHO、PRPF31、RP1、RDS及IMPDH1基因的关系。
方法
1.基因分型在3号染色体RHO基因上下游选取相距1cM的2个短串联重复序列STR:D3S3606与D3S1292第二代遗传标记进行多重PCR反应,STR引物序列5’-端加FAM荧光标记,根据荧光标记,采用ABI公司3100测序仪读取STR等位基因片段大小,收集数据后用Gene Mapper version 3.5软件包进行处理。
2.连锁分析和单倍型分析利用LINKAGE package 5.1软件包中的MLINK程序将每对引物与adRP家系致病基因位点进行两点连锁分析,根据下列标准判断遗传标记与疾病的连锁程度：LOD值≥+3,肯定连锁；LOD值≤-2,否定连锁；-2 3.测序利用Primer premier5.0软件设计引物,PCR产物纯化后上样,利用ABI PRISM(?)3100 Genetic Analyze测序仪对RHO基因第1-5外显子及外显子与内含子的交界处序列及PRPF31、RDS、IMPDH1基因多发突变位点的进行序列分析,测序结果与GenBank数据库中核酸序列进行比对。
4.限制性内切酶反应全部家系成员的RHO基因第5号外显子PCR纯化产物加入限制性内切酶NlaIVI,消化后取样于非变性聚丙烯酰胺凝胶(native-PAGE)中进行电泳分析,从而从另一角度证实RHO第5号外显子的碱基变异。
5.数据统计实验对研究中所发现的4个SNP位点：c.45G/A (rs7984)、c.70A/G (rs2269736)、(IVS6-78_IVS6-75del4CACA, rs57960425)及IVS6-31C/T(rs2303557)上的基因型与等位基因频率进行列表统计。因样本容量太小且样本中个体之间不是相互独立的,故未做χ2检验及等统计分析。
结果
1.5代22名成员中13人已确诊为视网膜色素变性,其中8名男性5名女性。第Ⅳ代年龄9岁(Ⅳ6),第Ⅴ代年龄6岁(V1),目前均已出现夜盲症状,但眼底检查及电生理检查尚正常。该家系为常染色体显性遗传性视网膜色素变性,家系患者间症状相似,即自幼出现夜盲,随年龄的增长,双眼视力逐渐减退,晚期多出现后囊性白内障,眼底改变表现为：视盘色泽呈蜡黄,视网膜血管变细,视网膜后极部广泛的骨细胞样色素沉着,黄斑光反射存在,视网膜电图杆锥细胞振幅减低,甚至熄灭。患病成员中除了视网膜色素变性和白内障外,无其他眼科疾病,也无其他异常症状。
2.对RHO基因进行两点连锁分析,结果显示当重组率θ=0时,D3S3606、D3S1292存在最大LOD值：3.61、4.55,其支持遗传标记D3S3606、D3S1292与该家系adRP疾病存在连锁；从单倍型分析中可见,D3S3606与D3S1292之间约的1 cM(里摩)区域与疾病呈共分离,因此提示该家系的致病基因可能在3号染色体上D3S3606与D3S1292之间相距1cM的区域,而该区域目前发现的唯一与adRP相关的致病基因是RHO。
3.RHO基因序列分析结果发现所有adRP患者RHO基因第5号外显子
347位密码子的第2碱基处均发生单个碱基替换(c.1040C>T),该位点呈杂合型,其碱基的变异导致脯氨酸(Pro)变为亮氨酸(Leu)。此外,家系成员中RHO基因外显子1非编码区存在2个多态位点：c.45G/A(rs7984),c.70A/G(rs2269736),统计发现,61.54%(8／13)患者共表达AA(rs7984).GG(rs2269736)基因型。而在PRPF31基因中,50%(11／22)家系成员存在PRPF31基因第6内含子4个碱基的缺失(IVS6.78_IVS6.75del4CACA,rs57960425),其中包括7例(53.8%)adRP患者和4例(44.4%)正常个体；50%(11／22)家系成员存在IVS6-31 C/T(rs2303557)变异,包括8例(61.5%)adRP患者和3例(33.3%)正常个体。RP1、RDS及IMPDH1基因的多发位点筛查未发现任何碱基变异。
4.限制性内切酶反应显示,所有家系的RP患者经NlaIV酶消化后产生5个片段：307bp.177bp.130bp.50bp及43bp,而正常个体只有4个片段：177bp和130bp.50bp.43bp,因而进一步验证了RHO基因第5号外显子347位密码子的第2碱基处发生了改变,且该位点的突变与疾病呈共分离。
结论
1.PRPF31.IMPDH1及RDS基因多发位点的碱基变异与该白族家系的adRP发病无相关。
2.RHO基因突变与该白族家系的致病基因存在连锁关系,其与adRP疾病呈共分离,所有家系患者均有RHO基因第5号外显子的错义突变(p.Pro347Leu),该突变与其致病相关。
3.RHO基因第1号外显子非编码区的两个SNP位点rs7984(AA). rs2269736(GG)纯合基因型的共表达与p.Pro347Leu突变致病可能存在疾病关联性。
Background
Autosomal dominant retinitis pigmentosa (adRP) is a clinically and genetically heterogeneous disorder. It can be transmitted as autosomal dominant RP (adRP), autosomal recessive RP (arRP), X-link RP (XLRP) and some with digenic or mitochondrial inheritance. RP is the most frequent form of inherited retinopathy, with an approximate incidence of 1 in 3500 individuals worldwide and over one million being affected. But to this day, there is no prevention or treatment available for it. Identification of additional loci as well as of the causative genes is the first step toward understanding the molecular basis of RP, and subsequently, toward the genetic counseling, prenatal diagnosis or treatment of this sight threatening problem. Studies show that over 70 loci were relative to the disfounction of human retinal photoreceptor, and now 53 loci have been identified. Therefore gene mapping of RP is still hot research in molecular genetics.
Of the 53 loci,19 have been determined in adRP, and rhodopsin (RHO)、PRPF31、RP1、RDS and IMPDH1 are more frequently reported as adRP gene in many populations. Although RHO and PRPF31 gene are common in Han Chinese, it has not been detected in patients from the Bai nationality, one of minority ethnic groups of southwest China. Up to now, there are 120 different mutations reported in RHOand many of which shows a point mutation. Studies have discovered that these mutations displayed different distribution in different population, such as in the west it accounts for 25%and of that 5.9%in Japan,7.7%in china. Pro23His was the most common mutation of RHO in South American while in Asian, all of the RHO mutation located in c-terminal and Pro347Lue was most commonly reported in the globe. PRPF31 gene, second only to see frequently except RHO gene, was firstly found in a large English adRP pedigree and mapped in chromosome by linkage analysis. Nowadays over 30 different mutations have been reported in PRPF3 gene that include missense, deletion and insertion and splice site alterations. The most frequent mutational site of PRPF31 gene was locating in exon5, exon6, exon7, exon8, exon11 and intron splice sites. Shown in data that RP1 gene was common in the west but rare in china, its mutation causing adRP accounted for 7%and exon4 (R677X) of this gene was the most frequent mutational site. Mutation in RDS gene may result many of retinal degeneration and today over 70 mutants of RDS were associated with adRP and autosomal dominant macula degeneration, of which accounting for 5%in adRP. RDS gene's mutations, including the most frequent mutational site (exonl) also characterized by territory disparation. The majority of these mutations were found in American or Norther Europe whereas rare in Asian. Mutations of IMPDH1 gene mapping in chromosome 7q32.1 was seldom in our country and its frequent mutational site was exon7, but the clinical symptom suffered from these mutants were early-onset and severiou.
As the reported from literatures, the mapping of RP disease-causing mutation was largely carried out through linkage analysis. Science in 1990s, Inglehearn and Greenberg have used the second generation genetic marks, short tandem repeat (STR) to perform linkage analysis then they found two novel loci in chromosome 7p and chromosome 17p. With the help of generation genetic marks, linkage analysis could make a fair decision in whether there would be a linkage relation between markers and disease locus and finally confirm a candidate for the studied pedigree.
Inherited disease holds a genetic predisposition in a pedigree, and it was a characteristic in genetic research to perform gene mapping by taking advantage of pedigrees especially from a big Chinese family. RP was charactered by genetic heterogeneity, affected individuals, even coming from a pedigree maybe harbor different disease-causing gene. The Bai (Pai) nationality, one of minority ethnic groups of southwest China shares its own culture feature and rarely contacts with others beyond toward to this region, of which the background was beneficial for linkage analysis. To hunt for the mutant gene in the Bai family will enrich the mutation spectrum of human RP gene in different ethnic groups and supply more information for the establishment of Chinese RP gene map and system of gene order structure or function.
Objective
To study the relationship between causative genes of a pedigree with adRP and RHO, PRPF31, RP1、RDS and IMPDH1 genes
Methods
1. Microsatellite markers D3S3606 and D3S1292, which closed to the RHO locus and with a distance approximately one-centimorgan (cM) on chromosome 3 were selected to perform genotyping. The size of allele was determined on the basis of an internal size standard, and data were analyzed using the Gene Mapper version 3.5 software package.
2. LOD scores for two-point linkage analysis between the disease locus and the genetic markers was performed with LINKAGE package 5.1. And the judgement of linkage degree according to the following criteria:if LOD score is large than or equal to 3, marker linkage to disease locus is certain; if LOD score less than negative or equal to 2, it dose not support linkage; if LOD score belongs to the others, it should be made a larger samples. In addition, Haplotype analysis was completed by using Cyrillic 2.1 software.
3. Primers were designed with Primer premier version 5.0 to amplify all coding region and intron splice sites of RHO and the hot mutation spot of the PFPR31、IMPDH1 and RDS gene. The PCR products were sequenced directly by ABI PRISM(?)3100 Genetic Analyze and the results were Blast with the sequence from GenBank database for mutation analysis.
4. Reaction of restriction enzyme was carried out for 391bp PCR products of exon5 of RHO amplified from 13 affected and 9 unaffected members withl U of NlaIV to confirm the results of sequencing.
5. Statistical analysis was not performed with SPSS13.0 software to test chi-square for SNPs rs7984, rs2269736, rs57960425 and rs2303557 because the sample size collected were too small and the related species were not independent.
Results
1. We identified and characterized a Bai adRP pedigree, of which 13 individuals were affected and 9 were unaffected members, However, during to younger ofⅣ4、Ⅳ5、Ⅳ6andⅤ1, there were no changes in their ERG or fundus examination, but a nyctalopia had been represented. The inheritance pattern in the pedigree is autosomal dominant, all of the affected individuals have a similar juvenile-onset night blindness, visual deterioration with growths and posterior subcapsular opacity in advanced stage, but no others syndrome were found except for these.
2. The maximum two-point LOD score obtained was 3.61 and 4.52 at a recombination fraction (0) of zero with markers D3S3606 and D3S1292, respectively. Haplotype analysis showed cosegregation one-centimorgan region harboring the RHO gene between the two markers with the disease, which indicates that the disease-caused gene locus is located in this region.
3. Direct sequencing of RHO revealed a heterozygous nucleotide substitution (c.1040C＞T) in exon 5, which was carried by all the affected individuals. Two single nucleotide polymorphisms rs7984 and rs2269736 were found in exon 1, and higher frequencies (61.54%) of genotypes AA of rs7984 and GG of rs2269736 were found in affected members of this pedigree. A four-base deletion at intron 6 of PRPF31 (IVS6-78_IVS6-75del4CACA) was observed in eleven members (50%), including seven (53.8%) adRP patients and four (44.4%) unaffected individuals. A variation IVS6-31 C/T was also found at intron 6 of PRPF31 in eight affectedmembers (61.5%) and three unaffected members (33.3%). No variations were found in IMPDH1 and RDS genes.
4. With digested by the restriction enzyme NlaIV, All affected individuals examined in the pedigree are heterozygous carriers who have all five bands at 307 bp,177 bp,130 bp,50 bp and 43 bp. The unaffected individuals are homozygous and have only the four lower bands (177 bp,130 bp,50 bp and 43 bp), which supported that c.1040C>T mutation was co-segregated with this disease.
Conclusion
1. The hot mutation spot of PRPF31、IIMPDH1 and RDS gene were not relative to the adRP in this Bai pedigree.
2. A c.1040C＞T (p.Pro3471eu) mutation in exon 5 of RHO was cosegregated with disease and responsible for the molecule-based pathogenesis in a Chinese Bai pedigree with adRP.
3. The co-expression of homozygotic genotype of single nucleotide polymorphisms rs7984 (AA) and rs2269736 (GG) may be associated with the onset of adRP in the Bai pedigree.
视网膜色素变性(retinitis pigmentosa, RP)是视网膜变性中最常见的一组以进行性光感受器细胞及视网膜色素上皮功能丧失为共同表现的致盲性眼病,其具有高度的遗传和表型异质性。根据RP遗传方式的不同,可将其分为常染色体显性遗传RP (autosomal dominant RP, adRP)、常染色体隐性遗传RP(autosomal recessive RP, arRP)和X伴性连锁遗传RP (X-lined RP, XLRP),少数表现为双基因突变遗传及线粒体遗传。当因缺乏家族史而无法确定其遗传方式时,则为散发型RP (sporadic RR,SRP),大多数SRP表现为arRP。经统计,引起adRP、arRP、XLRP的突变基因分别有20、26、2种。RP是发达国家工作年龄中致盲的最普遍原因,全球RP的发病率约为1／3500,已超过100万人受累,但目前尚无有效的预防和治疗措施,而对RP致病基因的确立则可为探讨RP发病机制,进行遗传咨询、产前诊断及基因治疗创造条件。研究表明,与人类光感受器功能障碍或变性有关的基因座约有70多个,目前已发现53个基因座与RP有关,因此对RP致病基因的定位研究仍然是分子遗传学研究的热点。
adRP是最常见的RP遗传方式,目前在已报道的53个基因座中,已确定19个与adRP有关,其中RHO、PRPF31、RP1、IMPDH1及RDS基因是引起adRP常见的突变基因。RHO与PRPF31基因是我国汉族RP人群中最常见的突变基因,但在白族人群中尚未见报道。至今,RHO基因已超过120种不同类型的突变被发现,在这些突变中,90%为单个碱基置换的点突变,一般突变范围不超过20个碱基对。研究发现,该基因突变存在种族差异,在欧美、日本、中国其突变所占adRP分别为25%、5.9%、7.7%,南美人群中最常见的RHO基因突变类型是Pro23His,而亚洲,所有已报道的RHO基因突变均集中在羧基末端(QVSPA), Pro347Lue是该区域中最多见的突变热点,也是全球性的多发突变位点。PRPF31基因是仅次于RHO基因座的常见adRP基因,其最先是在一个英国adRP大家族通过连锁分析发现并将其定位在染色体19q13.4, PRPF31基因突变包括错义突变、缺失、插入及剪接位点的改变,目前已有30个不同位点的突变被发现,其较多见的突变位点位于外显子5、外显子6、外显子7、外显子8、外显子11及内含子与外显子交界处。据统计,在美国等西方国家RP1突变是较常见的,占所有RP的7%,其中以位于外显子4的错义突变(R677X)多见,在我国,其突变较少见。RDS突变可引起很多类型的视网膜变性,目前已发现超过70个RDS基因突变与adRP和常染色体显性黄斑变性(adMD)有关,其中引起adRP的突变位点仅占5%。RDS突变所致的adRP有地区差异,在美国及北欧较多见,在我国等亚洲国家较少见,RDS基因突变多位于外显子1。IMPDH1基因突变多见于外显子7,目前国内外对IMPDH1基因的突变报道尚不多,但其突变所致的adRP发病早,且严重。
在这些已发现的RP基因座中大多数是通过家系连锁分析的方法定位的,连锁分析是一种成熟的基因定位克隆技术,90年代初Inglehearn、Greenberg等就利用短串联重复序列(short tandem repeat,STR)遗传标记进行连锁分析,分别在染色体7p、17P上发现了新的adRP致病基因,随后也相继有报道。该技术是其以二代或二代以上的家系材料为基础,利用人类基因组中存在的遗传标记进行分析,观察标记位点与疾病致病基因位点在家系内是否呈共分离,并计算出遗传距离及连锁程度,从而确定致病的候选基因。
遗传病具有一定的家族遗传倾向,利用家系对遗传性疾病的研究是基因定位的一大特色,也是发挥我国人口资源优势的一大特色。RP致病基因的突变是多种多样的,特别是在不同地区、不同民族中,不同基因的突变可导致RP,相同基因的不同突变也可引起RP。白族是我国西南地区一个不同于汉族的少数民族,其世代迁移少,是相对封闭的种族,具有良好的单基因疾病遗传背景,对其致病基因的定位研究,将丰富我国RP基因的突变图谱,为创建我国RP人群遗传图谱及基因序列结构功能信息系统提供更多信息。
研究目的
确定该白族adRP家系的发病与RHO、PRPF31、RP1、RDS及IMPDH1基因的关系。
方法
1.基因分型在3号染色体RHO基因上下游选取相距1cM的2个短串联重复序列STR:D3S3606与D3S1292第二代遗传标记进行多重PCR反应,STR引物序列5’-端加FAM荧光标记,根据荧光标记,采用ABI公司3100测序仪读取STR等位基因片段大小,收集数据后用Gene Mapper version 3.5软件包进行处理。
2.连锁分析和单倍型分析利用LINKAGE package 5.1软件包中的MLINK程序将每对引物与adRP家系致病基因位点进行两点连锁分析,根据下列标准判断遗传标记与疾病的连锁程度：LOD值≥+3,肯定连锁；LOD值≤-2,否定连锁；-2
4.限制性内切酶反应全部家系成员的RHO基因第5号外显子PCR纯化产物加入限制性内切酶NlaIVI,消化后取样于非变性聚丙烯酰胺凝胶(native-PAGE)中进行电泳分析,从而从另一角度证实RHO第5号外显子的碱基变异。
5.数据统计实验对研究中所发现的4个SNP位点：c.45G/A (rs7984)、c.70A/G (rs2269736)、(IVS6-78_IVS6-75del4CACA, rs57960425)及IVS6-31C/T(rs2303557)上的基因型与等位基因频率进行列表统计。因样本容量太小且样本中个体之间不是相互独立的,故未做χ2检验及等统计分析。
结果
1.5代22名成员中13人已确诊为视网膜色素变性,其中8名男性5名女性。第Ⅳ代年龄9岁(Ⅳ6),第Ⅴ代年龄6岁(V1),目前均已出现夜盲症状,但眼底检查及电生理检查尚正常。该家系为常染色体显性遗传性视网膜色素变性,家系患者间症状相似,即自幼出现夜盲,随年龄的增长,双眼视力逐渐减退,晚期多出现后囊性白内障,眼底改变表现为：视盘色泽呈蜡黄,视网膜血管变细,视网膜后极部广泛的骨细胞样色素沉着,黄斑光反射存在,视网膜电图杆锥细胞振幅减低,甚至熄灭。患病成员中除了视网膜色素变性和白内障外,无其他眼科疾病,也无其他异常症状。
2.对RHO基因进行两点连锁分析,结果显示当重组率θ=0时,D3S3606、D3S1292存在最大LOD值：3.61、4.55,其支持遗传标记D3S3606、D3S1292与该家系adRP疾病存在连锁；从单倍型分析中可见,D3S3606与D3S1292之间约的1 cM(里摩)区域与疾病呈共分离,因此提示该家系的致病基因可能在3号染色体上D3S3606与D3S1292之间相距1cM的区域,而该区域目前发现的唯一与adRP相关的致病基因是RHO。
3.RHO基因序列分析结果发现所有adRP患者RHO基因第5号外显子
347位密码子的第2碱基处均发生单个碱基替换(c.1040C>T),该位点呈杂合型,其碱基的变异导致脯氨酸(Pro)变为亮氨酸(Leu)。此外,家系成员中RHO基因外显子1非编码区存在2个多态位点：c.45G/A(rs7984),c.70A/G(rs2269736),统计发现,61.54%(8／13)患者共表达AA(rs7984).GG(rs2269736)基因型。而在PRPF31基因中,50%(11／22)家系成员存在PRPF31基因第6内含子4个碱基的缺失(IVS6.78_IVS6.75del4CACA,rs57960425),其中包括7例(53.8%)adRP患者和4例(44.4%)正常个体；50%(11／22)家系成员存在IVS6-31 C/T(rs2303557)变异,包括8例(61.5%)adRP患者和3例(33.3%)正常个体。RP1、RDS及IMPDH1基因的多发位点筛查未发现任何碱基变异。
4.限制性内切酶反应显示,所有家系的RP患者经NlaIV酶消化后产生5个片段：307bp.177bp.130bp.50bp及43bp,而正常个体只有4个片段：177bp和130bp.50bp.43bp,因而进一步验证了RHO基因第5号外显子347位密码子的第2碱基处发生了改变,且该位点的突变与疾病呈共分离。
结论
1.PRPF31.IMPDH1及RDS基因多发位点的碱基变异与该白族家系的adRP发病无相关。
2.RHO基因突变与该白族家系的致病基因存在连锁关系,其与adRP疾病呈共分离,所有家系患者均有RHO基因第5号外显子的错义突变(p.Pro347Leu),该突变与其致病相关。
3.RHO基因第1号外显子非编码区的两个SNP位点rs7984(AA). rs2269736(GG)纯合基因型的共表达与p.Pro347Leu突变致病可能存在疾病关联性。
Background
Autosomal dominant retinitis pigmentosa (adRP) is a clinically and genetically heterogeneous disorder. It can be transmitted as autosomal dominant RP (adRP), autosomal recessive RP (arRP), X-link RP (XLRP) and some with digenic or mitochondrial inheritance. RP is the most frequent form of inherited retinopathy, with an approximate incidence of 1 in 3500 individuals worldwide and over one million being affected. But to this day, there is no prevention or treatment available for it. Identification of additional loci as well as of the causative genes is the first step toward understanding the molecular basis of RP, and subsequently, toward the genetic counseling, prenatal diagnosis or treatment of this sight threatening problem. Studies show that over 70 loci were relative to the disfounction of human retinal photoreceptor, and now 53 loci have been identified. Therefore gene mapping of RP is still hot research in molecular genetics.
Of the 53 loci,19 have been determined in adRP, and rhodopsin (RHO)、PRPF31、RP1、RDS and IMPDH1 are more frequently reported as adRP gene in many populations. Although RHO and PRPF31 gene are common in Han Chinese, it has not been detected in patients from the Bai nationality, one of minority ethnic groups of southwest China. Up to now, there are 120 different mutations reported in RHOand many of which shows a point mutation. Studies have discovered that these mutations displayed different distribution in different population, such as in the west it accounts for 25%and of that 5.9%in Japan,7.7%in china. Pro23His was the most common mutation of RHO in South American while in Asian, all of the RHO mutation located in c-terminal and Pro347Lue was most commonly reported in the globe. PRPF31 gene, second only to see frequently except RHO gene, was firstly found in a large English adRP pedigree and mapped in chromosome by linkage analysis. Nowadays over 30 different mutations have been reported in PRPF3 gene that include missense, deletion and insertion and splice site alterations. The most frequent mutational site of PRPF31 gene was locating in exon5, exon6, exon7, exon8, exon11 and intron splice sites. Shown in data that RP1 gene was common in the west but rare in china, its mutation causing adRP accounted for 7%and exon4 (R677X) of this gene was the most frequent mutational site. Mutation in RDS gene may result many of retinal degeneration and today over 70 mutants of RDS were associated with adRP and autosomal dominant macula degeneration, of which accounting for 5%in adRP. RDS gene's mutations, including the most frequent mutational site (exonl) also characterized by territory disparation. The majority of these mutations were found in American or Norther Europe whereas rare in Asian. Mutations of IMPDH1 gene mapping in chromosome 7q32.1 was seldom in our country and its frequent mutational site was exon7, but the clinical symptom suffered from these mutants were early-onset and severiou.
As the reported from literatures, the mapping of RP disease-causing mutation was largely carried out through linkage analysis. Science in 1990s, Inglehearn and Greenberg have used the second generation genetic marks, short tandem repeat (STR) to perform linkage analysis then they found two novel loci in chromosome 7p and chromosome 17p. With the help of generation genetic marks, linkage analysis could make a fair decision in whether there would be a linkage relation between markers and disease locus and finally confirm a candidate for the studied pedigree.
Inherited disease holds a genetic predisposition in a pedigree, and it was a characteristic in genetic research to perform gene mapping by taking advantage of pedigrees especially from a big Chinese family. RP was charactered by genetic heterogeneity, affected individuals, even coming from a pedigree maybe harbor different disease-causing gene. The Bai (Pai) nationality, one of minority ethnic groups of southwest China shares its own culture feature and rarely contacts with others beyond toward to this region, of which the background was beneficial for linkage analysis. To hunt for the mutant gene in the Bai family will enrich the mutation spectrum of human RP gene in different ethnic groups and supply more information for the establishment of Chinese RP gene map and system of gene order structure or function.
Objective
To study the relationship between causative genes of a pedigree with adRP and RHO, PRPF31, RP1、RDS and IMPDH1 genes
Methods
1. Microsatellite markers D3S3606 and D3S1292, which closed to the RHO locus and with a distance approximately one-centimorgan (cM) on chromosome 3 were selected to perform genotyping. The size of allele was determined on the basis of an internal size standard, and data were analyzed using the Gene Mapper version 3.5 software package.
2. LOD scores for two-point linkage analysis between the disease locus and the genetic markers was performed with LINKAGE package 5.1. And the judgement of linkage degree according to the following criteria:if LOD score is large than or equal to 3, marker linkage to disease locus is certain; if LOD score less than negative or equal to 2, it dose not support linkage; if LOD score belongs to the others, it should be made a larger samples. In addition, Haplotype analysis was completed by using Cyrillic 2.1 software.
3. Primers were designed with Primer premier version 5.0 to amplify all coding region and intron splice sites of RHO and the hot mutation spot of the PFPR31、IMPDH1 and RDS gene. The PCR products were sequenced directly by ABI PRISM(?)3100 Genetic Analyze and the results were Blast with the sequence from GenBank database for mutation analysis.
4. Reaction of restriction enzyme was carried out for 391bp PCR products of exon5 of RHO amplified from 13 affected and 9 unaffected members withl U of NlaIV to confirm the results of sequencing.
5. Statistical analysis was not performed with SPSS13.0 software to test chi-square for SNPs rs7984, rs2269736, rs57960425 and rs2303557 because the sample size collected were too small and the related species were not independent.
Results
1. We identified and characterized a Bai adRP pedigree, of which 13 individuals were affected and 9 were unaffected members, However, during to younger ofⅣ4、Ⅳ5、Ⅳ6andⅤ1, there were no changes in their ERG or fundus examination, but a nyctalopia had been represented. The inheritance pattern in the pedigree is autosomal dominant, all of the affected individuals have a similar juvenile-onset night blindness, visual deterioration with growths and posterior subcapsular opacity in advanced stage, but no others syndrome were found except for these.
2. The maximum two-point LOD score obtained was 3.61 and 4.52 at a recombination fraction (0) of zero with markers D3S3606 and D3S1292, respectively. Haplotype analysis showed cosegregation one-centimorgan region harboring the RHO gene between the two markers with the disease, which indicates that the disease-caused gene locus is located in this region.
3. Direct sequencing of RHO revealed a heterozygous nucleotide substitution (c.1040C＞T) in exon 5, which was carried by all the affected individuals. Two single nucleotide polymorphisms rs7984 and rs2269736 were found in exon 1, and higher frequencies (61.54%) of genotypes AA of rs7984 and GG of rs2269736 were found in affected members of this pedigree. A four-base deletion at intron 6 of PRPF31 (IVS6-78_IVS6-75del4CACA) was observed in eleven members (50%), including seven (53.8%) adRP patients and four (44.4%) unaffected individuals. A variation IVS6-31 C/T was also found at intron 6 of PRPF31 in eight affectedmembers (61.5%) and three unaffected members (33.3%). No variations were found in IMPDH1 and RDS genes.
4. With digested by the restriction enzyme NlaIV, All affected individuals examined in the pedigree are heterozygous carriers who have all five bands at 307 bp,177 bp,130 bp,50 bp and 43 bp. The unaffected individuals are homozygous and have only the four lower bands (177 bp,130 bp,50 bp and 43 bp), which supported that c.1040C>T mutation was co-segregated with this disease.
Conclusion
1. The hot mutation spot of PRPF31、IIMPDH1 and RDS gene were not relative to the adRP in this Bai pedigree.
2. A c.1040C＞T (p.Pro3471eu) mutation in exon 5 of RHO was cosegregated with disease and responsible for the molecule-based pathogenesis in a Chinese Bai pedigree with adRP.
3. The co-expression of homozygotic genotype of single nucleotide polymorphisms rs7984 (AA) and rs2269736 (GG) may be associated with the onset of adRP in the Bai pedigree.
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[44]Zhao C, Lu S, Zhou X, et al. A novel locus (RP33) for autosomal dominant retinitis pigmentosa mapping to chromosomal region 2cen-q12.1.[J]. Hum Genet,2006,119(6):617-623.
[45]Punzo C, Kornacker K, Cepko C L. Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa.[J]. Nat Neurosci,2009,12(1):44-52.
[46]Fujiki K, Hotta Y, Hayakawa M, et al. Point mutations of rhodopsin gene found in Japanese families with autosomal dominant retinitis pigmentosa (ADRP).[J]. Jpn J Hum Genet,1992,37(2):125-132.
[47]Dikshit M, Agarwal R. Mutation analysis of codons 345 and 347 of rhodopsin gene in Indian retinitis pigmentosa patients.[J]. J Genet,2001,80(2):111-116.
[48]Roberts L, Ramesar R, Greenberg J. Low frequency of rhodopsin mutations in South African patients with autosomal dominant retinitis pigmentosa.[J]. Clin Genet,2000,58(1):77-78.
[49]Kucinskas V, Payne A M, Ambrasiene D, et al. Molecular genetic study of autosomal dominant retinitis pigmentosa in Lithuanian patients.[J]. Hum Hered,1999,49(2):71-74.
[50]Chan W M, Yeung K Y, Pang C P, et al. Rhodopsin mutations in Chinese patients with retinitis pigmentosa.[J]. Br J Ophthalmol,2001,85(9):1046-1048.
[51]Dryja T P, Mcgee T L, Hahn L B, et al. Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa.[J]. N Engl J Med,1990,323(19):1302-1307.
[52]Chen J, Makino C L, Peachey N S, et al. Mechanisms of rhodopsin inactivation in vivo as revealed by a COOH-terminal truncation mutant.[J]. Science,1995, 267(5196):374-377.
[53]Mendez A, Burns M E, Roca A, et al. Rapid and reproducible deactivation of rhodopsin requires multiple phosphorylation sites.[J]. Neuron,2000, 28(1):153-164.
[54]Li T, Snyder W K, Olsson J E, et al. Transgenic mice carrying the dominant rhodopsin mutation P347S:evidence for defective vectorial transport of rhodopsin to the outer segments. [J]. Proc Natl Acad Sci U S A,1996,93(24):14176-14181.
[55]Mendes H F, Cheetham M E. Pharmacological manipulation of gain-of-function and dominant-negative mechanisms in rhodopsin retinitis pigmentosa.[J]. Hum Mol Genet,2008,17(19):3043-3054.
[56]Sandberg M A, Weigel-Difranco C, Dryja T P, et al. Clinical expression correlates with location of rhodopsin mutation in dominant retinitis pigmentosa.[J]. Invest Ophthalmol Vis Sci,1995,36(9):1934-1942.
[57]Zhang X L, Liu M, Meng X H, et al. Mutational analysis of the rhodopsin gene in Chinese ADRP families by conformation sensitive gel electrophoresis.[J]. Life Sci,2006,78(13):1494-1498.
[58]Lim K P, Yip S P, Cheung S C, et al. Novel PRPF31 and PRPH2 mutations and co-occurrence of PRPF31 and RHO mutations in Chinese patients with retinitis pigmentosa.[J]. Arch Ophthalmol,2009,127(6):784-790.
[59]李婧,潘玉春,李亦学,et al.人类基因组单核苷酸多态性和单体型的分析及应用[J].遗传学报,2005,32(8)：879-889.
[60]Ando Y, Ohmori M, Ohtake H, et al. Mutation screening and haplotype analysis of the rhodopsin gene locus in Japanese patients with retinitis pigmentosa.[J]. MolVis,2007,13:1038-1044.
[61]Kokame K, Matsumoto M, Soejima K, et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. [J]. Proc Natl Acad Sci U S A,2002,99(18):11902-11907.
[62]Plaimauer B, Fuhrmann J, Mohr G, et al. Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation.[J].Blood,2006,107(1):118-125.
[63]The International HapMap Project.[J]. Nature,2003,426(6968):789-796.
[64]Wang L, Ribaudo M, Zhao K, et al. Novel deletion in the pre-mRNA splicing gene PRPF31 causes autosomal dominant retinitis pigmentosa in a large Chinese family.[J]. Am J Med Genet A,2003,121A(3):235-239.
[65]Liu J Y, Dai X, Sheng J, et al. Identification and functional characterization of a novel splicing mutation in RP gene PRPF31.[J]. Biochem Biophys Res Commun,2008,367(2):420-426.
[66]Jr Logsdon J M. The recent origins of spliceosomal introns revisited.[J]. Curr Opin Genet Dev,1998,8(6):637-648.
[67]Sachse C, Brockmoller J, Bauer S, et al. Functional significance of a C->A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine.[J]. Br J Clin Pharmacol,1999,47(4):445-449.
[68]Huang M, Han Y, Zhang X, et al. An intron polymorphism in the CXCL16 gene is associated with increased risk of coronary artery disease in Chinese Han population:A large angiography-based study.[J]. Atherosclerosis,2009.
[1]Yong RY, Chee CK, Yap EP. A two-stage approach identifies a Q344X mutation in the rhodopsin gene of a Chinese Singaporean family with autosomal dominant retinitis pigmentosa[J]. Ann Acad Med Singapore,2005, 34(1):94-99
[2]Daiger SP, Bowne SJ, Sullivan LS. Perspective on genes and mutations causing retinitis pigmentosa[J]. Arch Ophthalmol,2007,125(2):151-158
[3]Mordes D, Luo X, Kar A, et al. Pre-mRNA splicing and retinitis pigmentosa[J]. Mol Vis,2006,12:1259-1271
[4]Xia K, Zheng D, Pan Q, et al. A novel PRPF31 splice-site mutation in a Chinese family with autosomal dominant retinitis pigmentosa[J]. Mol Vis, 2004,10:361-365
[5]陆莎莎,赵晨,崔云,等.我国常染色体显性遗传视网膜色素变性家系中PRPF31基因新的剪切位点突变[J].中华眼科杂志,2005,40(4)：305-311
[6]Liu JY, Dai X, Sheng J, et al. Identification and functional characterization of a novel splicing mutation in RP gene PRPF31[J]. Biochem Biophys Res Commun,2008,367(2):420-426
[7]Chakarova CF, Cherninkova S, Tournev I, et al. Molecular genetics of retinitis pigmentosa in two Romani (Gypsy) families[J]. Mol Vis,2006,12:909-914
[8]Makarova OV, Makarov EM, Liu S, et al. Protein 61K, encoded by a gene (PRPF31) linked to autosomal dominant retinitis pigmentosa, is required for U4/U6*U5 tri-snRNP formation and pre-mRNA splicing[J]. EMBO J,2002, 21(5):1148-1157
[9]Schaffert N, Hossbach M, Heintzmann R, et al. RNAi knockdown of hPrp31 leads to an accumulation of U4/U6 di-snRNPs in Cajal bodies [J]. EMBO J, 2004,23(15):3000-3009
[10]Wilkie SE, Vaclavik V, Wu H, et al. Disease mechanism for retinitis pigmentosa (RP11) caused by missense mutations in the splicing factor gene PRPF31[J]. Mol Vis,2008,14:683-690
[11]Gamundi MJ, Hernan I, Muntanyola M, et al. Transcriptional expression of cis-acting and trans-acting splicing mutations cause autosomal dominant retinitis pigmentosa[J]. Hum Mutat,2008,29(6):869-878
[12]Graziotto JJ, Inglehearn CF, Pack MA, et al. Decreased levels of the RNA splicing factor Prpf3 in mice and zebrafish do not cause photoreceptor degeneration[J]. Invest Ophthalmol Vis Sci,2008,49(9):3830-3838
[13]Testa F, Ziviello C, Rinaldi M, et al. Clinical phenotype of an Italian family with a new mutation in the PRPF8 gene[J]. Eur J Ophthalmol,2006, 16(5):779-781
[14]Walia S, Fishman GA, Zernant-Rajang J, et al. Phenotypic expression of a PRPF8 gene mutation in a Large African American family [J]. Arch Ophthalmol,2008,126(8):1127-1132
[15]Maita H, Kitaura H, Keen TJ, et al. PAP-1, the mutated gene underlying the RP9 form of dominant retinitis pigmentosa, is a splicing factor [J]. Exp Cell Res,2004,300(2):283-296
[16]Daiger SP, Sullivan LS, Gire Al, et al. Mutations in known genes account for 58%of autosomal dominant retinitis pigmentosa (adRP)[J]. Adv Exp Med Biol, 2008,613:203-209
[17]Schuster A, Weisschuh N, Jagle H, et al. Novel rhodopsin mutations and genotype-phenotype correlation in patients with autosomal dominant retinitis pigmentosa[J]. Br J Ophthalmol,2005,89(10):1258-1264
[18]Grondahl J, Riise R, Heiberg A, et al. Autosomal dominant retinitis pigmentosa in Norway:a 20-year clinical follow-up study with molecular genetic analysis. Two novel rhodopsin mutations:1003delG and 1179F[J]. Acta Ophthalmol Scand,2007,85(3):287-297
[19]Ando Y, Ohmori. M, Ohtake H, et al. Mutation screening and haplotype analysis of the rhodopsin gene locus in Japanese patients with retinitis pigmentosa.[J]. Mol Vis,2007,13:1038-1044
[20]Gao J, Cheon K, Nusinowitz S, et al. Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalizatiori in mice with targeted disruption of the retinitis pigmentosa-1 (Rpl) gene[J]. Proc Natl Acad Sci USA,2002,99(8):5698-5703
[21]Liu Q, Zuo J, Pierce EA. The retinitis pigmentosa 1 protein is a photoreceptor microtubule-associated protein[J]. JNeurosci,2004,24(29):6427-6436
[22]Sheng X, Zhang X, Wu W, et al. Variants of RP1 gene in Chinese patients with autosomal dominant retinitis pigmentosa[J]. Can J Ophthalmol,2008, 43(2):208-212
[23]Khaliq S, Abid A, Ismail M, et al. Novel association of RP1 gene mutations with autosomal recessive retinitis pigmentosa[J]. J Med Genet,2005, 42(5):436-438
[24]Farjo R, Skaggs JS, Nagel BA, et al. Retention of function without normal disc morphogenesis occurs in cone but not rod photoreceptors[J]. J Cell Biol,2006, 173 (1):59-68
[25]崔云,赵堪兴,王立,等.视网膜色素变性遗传致病基因peripherin/RDS的突变筛选[J].眼科研究,2002,20(5)：385-387
[26]Leroy BP, Kailasanathan A, de Laey JJ, et al. Intrafamilial phenotypic variability in families with RDS mutations:exclusion of ROM1 as a genetic modifier for those with retinitis pigmentosa[J]. Br J Ophthalmol,2007, 91(1):89-93
[27]Boon CJ, Den HA, Hoyng CB, et al. The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene[J]. Prog Retin Eye Res,2008, 27(2):213-235
[28]Xi Q, Pauer GJ, Ball SL, et al. Interaction between the photoreceptor-specific tubby-like protein 1 and the neuronal-specific GTPase dynamin-1[J]. Invest Ophthalmol Vis Sci,2007,48(6):2837-2844
[29]Abbasi AH, Garzozi HJ, Ben-yosef T. A novel splice-site mutation of TULP1 underlies severe early-onset retinitis pigmentosa in a consanguineous Israeli Muslim Arab family [J]. Mol Vis,2008,14:675-682
[30]Shastry BS. Evaluation of the common variants of the ABCA4 gene in families with Stargards disease and autosomal recessive retinitis pigmentosa[J]. Int J MolMed,2008,21(6):715-720
[31]Fingert JH, Oh K, Chung M, et al. Association of a novel mutation in the retinol dehydrogenase 12 (RDH12) gene with autosomal dominant retinitis pigmentosa[J]. Arch Ophthalmol,2008,126(9):1301-1307
[32]Papaioannou M, Chakarova CF, Prescott DC, et al. A new locus (RP31) for autosomal dominant retinitis pigmentosa maps to chromosome 9p[J]. Hum Genet,2005,118(3-4):501-503
[33]Zhao C, Lu S, Zhou X, et al. A novel locus (RP33) for autosomal dominant retinitis pigmentosa mapping to chromosomal region 2cen-q12.1[J]. Hum Genet,2006,119(6):617-623
[34]Grover S, Fishman GA, Stone EM. A novel IMPDH1 mutation (Arg23 1Pro) in a family with a severe form of autosomal dominant retinitis pigmentosa[J]. Ophthalmology,2004,111 (10):1910-1916
[35]于永斌,杨洪滨,徐洋,等.视网膜色素变性一家系与IMPDH1基因突变相关[J].眼科新进展,2007,27(9)：649-652
[36]Mortimer SE, Hedstrom L. Autosomal dominant retinitis pigmentosa mutations in inosine 5'-monophosphate dehydrogenase type Ⅰ disrupt nucleic acid binding[J]. Biochem J,2005,390(Ptl):41-47
[37]Bowne SJ, Liu Q, Sullivan LS, et al. Why do mutations in the ubiquitously expressed housekeeping gene IMPDH1 cause retina-specific photoreceptor degeneration[J]. Invest Ophthalmol Vis Sci,2006,47(9):3754-3765
[38]Wang DY, Chan WM, Tam PO, et al. Genetic markers for retinitis pigmentosa.[J]. Hong Kong Med J,2005,11(4):281-288
[2]Yong R Y, Chee C K, Yap E P. A two-stage approach identifies a Q344X mutation in the rhodopsin gene of a Chinese Singaporean family with autosomal dominant retinitis pigmentosa.[J]. Ann Acad Med Singapore,2005, 34(1):94-99.
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[11]Schuster A, Weisschuh N, Jagle H, et al. Novel rhodopsin mutations and genotype-phenotype correlation in patients with autosomal dominant retinitis pigmentosa.[J]. Br J Ophthalmol,2005,89(10):1258-1264.
[12]Grondahl J, Riise R, Heiberg A, et al. Autosomal dominant retinitis pigmentosa in Norway:a 20-year clinical follow-up study with molecular genetic analysis. Two novel rhodopsin mutations:1003delG and I179F.[J]. Acta Ophthalmol Scand,2007,85(3):287-297.
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[17]陆莎莎,赵晨,崔云,et al.我国常染色体显性遗传视网膜色素变性家系中PRPF31基因新的剪切位点突变[J].中华眼科杂志,2005：305-311.
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[21]Schaffert N, Hossbach M, Heintzmann R, et al. RNAi knockdown of hPrp31 leads to an accumulation of U4/U6 di-snRNPs in Cajal bodies.[J]. EMBO J,2004,23(15):3000-3009.
[22]Wilkie S E, Vaclavik V, Wu H, et al. Disease mechanism for retinitis pigmentosa (RP11) caused by missense mutations in the splicing factor gene PRPF31.[J]. Mol Vis,2008,14:683-690.
[23]Farjo R, Skaggs J S, Nagel B A, et al. Retention of function without normal disc morphogenesis occurs in cone but not rod photoreceptors.[J]. J Cell Biol,2006,173(1):59-68.
[24]崔云,赵堪兴,王立,et al.视网膜色素变性遗传致病基因peripherin/RDS的突变筛选[J].眼科研究,2002：385-387.
[25]Leroy B P, Kailasanathan A, De L J, et al. Intrafamilial phenotypic variability in families with RDS mutations:exclusion of ROM 1 as a genetic modifier for those with retinitis pigmentosa.[J]. Br J Ophthalmol,2007,91(1):89-93.
[26]Boon C J, Den H A, Hoyng C B, et al. The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene.[J]. Prog Retin Eye Res,2008,27(2):213-235.
[27]Grover S, Fishman G A, Stone E M. A novel IMPDH1 mutation (Arg231Pro) in a family with a severe form of autosomal dominant retinitis pigmentosa.[J]. Ophthalmology,2004,111(10):1910-1916.
[28]杨洪滨等于永斌.视网膜色素变性一家系与IMPDH1基因突变相关△[J].眼科学进展,2007,第27卷(第9期).
[29]Mortimer S E, Hedstrom L. Autosomal dominant retinitis pigmentosa mutations in inosine 5'-monophosphate dehydrogenase type I disrupt nucleic acid binding.[J]. Biochem J,2005,390(Pt 1):41-47.
[30]Bowne S J, Liu Q, Sullivan L S, et al. Why do mutations in the ubiquitously expressed housekeeping gene IMPDH1 cause retina-specific photoreceptor degeneration?[J]. Invest Ophthalmol Vis Sci,2006,47(9):3754-3765.
[31]Gao J, Cheon K, Nusinowitz S, et al. Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa-1 (Rpl) gene.[J]. Proc Natl Acad Sci U S A,2002,99(8):5698-5703.
[32]Liu Q, Zuo J, Pierce E A. The retinitis pigmentosa 1 protein is a photoreceptor microtubule-associated protein.[J]. J Neurosci,2004,24(29):6427-6436.
[33]Sheng X, Zhang X, Wu W, et al. Variants of RP1 gene in Chinese patients with autosomal dominant retinitis pigmentosa.[J]. Can J Ophthalmol,2008, 43(2):208-212.
[34]Khaliq S, Abid A, Ismail M, et al. Novel association of RP1 gene mutations with autosomal recessive retinitis pigmentosa.[J]. J Med Genet,2005, 42(5):436-438.
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[43]Papaioannou M, Chakarova C F, Prescott D C, et al. A new locus (RP31) for autosomal dominant retinitis pigmentosa maps to chromosome 9p.[J]. Hum Genet,2005,118(3-4):501-503.
[44]Zhao C, Lu S, Zhou X, et al. A novel locus (RP33) for autosomal dominant retinitis pigmentosa mapping to chromosomal region 2cen-q12.1.[J]. Hum Genet,2006,119(6):617-623.
[45]Punzo C, Kornacker K, Cepko C L. Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa.[J]. Nat Neurosci,2009,12(1):44-52.
[46]Fujiki K, Hotta Y, Hayakawa M, et al. Point mutations of rhodopsin gene found in Japanese families with autosomal dominant retinitis pigmentosa (ADRP).[J]. Jpn J Hum Genet,1992,37(2):125-132.
[47]Dikshit M, Agarwal R. Mutation analysis of codons 345 and 347 of rhodopsin gene in Indian retinitis pigmentosa patients.[J]. J Genet,2001,80(2):111-116.
[48]Roberts L, Ramesar R, Greenberg J. Low frequency of rhodopsin mutations in South African patients with autosomal dominant retinitis pigmentosa.[J]. Clin Genet,2000,58(1):77-78.
[49]Kucinskas V, Payne A M, Ambrasiene D, et al. Molecular genetic study of autosomal dominant retinitis pigmentosa in Lithuanian patients.[J]. Hum Hered,1999,49(2):71-74.
[50]Chan W M, Yeung K Y, Pang C P, et al. Rhodopsin mutations in Chinese patients with retinitis pigmentosa.[J]. Br J Ophthalmol,2001,85(9):1046-1048.
[51]Dryja T P, Mcgee T L, Hahn L B, et al. Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa.[J]. N Engl J Med,1990,323(19):1302-1307.
[52]Chen J, Makino C L, Peachey N S, et al. Mechanisms of rhodopsin inactivation in vivo as revealed by a COOH-terminal truncation mutant.[J]. Science,1995, 267(5196):374-377.
[53]Mendez A, Burns M E, Roca A, et al. Rapid and reproducible deactivation of rhodopsin requires multiple phosphorylation sites.[J]. Neuron,2000, 28(1):153-164.
[54]Li T, Snyder W K, Olsson J E, et al. Transgenic mice carrying the dominant rhodopsin mutation P347S:evidence for defective vectorial transport of rhodopsin to the outer segments. [J]. Proc Natl Acad Sci U S A,1996,93(24):14176-14181.
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[56]Sandberg M A, Weigel-Difranco C, Dryja T P, et al. Clinical expression correlates with location of rhodopsin mutation in dominant retinitis pigmentosa.[J]. Invest Ophthalmol Vis Sci,1995,36(9):1934-1942.
[57]Zhang X L, Liu M, Meng X H, et al. Mutational analysis of the rhodopsin gene in Chinese ADRP families by conformation sensitive gel electrophoresis.[J]. Life Sci,2006,78(13):1494-1498.
[58]Lim K P, Yip S P, Cheung S C, et al. Novel PRPF31 and PRPH2 mutations and co-occurrence of PRPF31 and RHO mutations in Chinese patients with retinitis pigmentosa.[J]. Arch Ophthalmol,2009,127(6):784-790.
[59]李婧,潘玉春,李亦学,et al.人类基因组单核苷酸多态性和单体型的分析及应用[J].遗传学报,2005,32(8)：879-889.
[60]Ando Y, Ohmori M, Ohtake H, et al. Mutation screening and haplotype analysis of the rhodopsin gene locus in Japanese patients with retinitis pigmentosa.[J]. MolVis,2007,13:1038-1044.
[61]Kokame K, Matsumoto M, Soejima K, et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. [J]. Proc Natl Acad Sci U S A,2002,99(18):11902-11907.
[62]Plaimauer B, Fuhrmann J, Mohr G, et al. Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation.[J].Blood,2006,107(1):118-125.
[63]The International HapMap Project.[J]. Nature,2003,426(6968):789-796.
[64]Wang L, Ribaudo M, Zhao K, et al. Novel deletion in the pre-mRNA splicing gene PRPF31 causes autosomal dominant retinitis pigmentosa in a large Chinese family.[J]. Am J Med Genet A,2003,121A(3):235-239.
[65]Liu J Y, Dai X, Sheng J, et al. Identification and functional characterization of a novel splicing mutation in RP gene PRPF31.[J]. Biochem Biophys Res Commun,2008,367(2):420-426.
[66]Jr Logsdon J M. The recent origins of spliceosomal introns revisited.[J]. Curr Opin Genet Dev,1998,8(6):637-648.
[67]Sachse C, Brockmoller J, Bauer S, et al. Functional significance of a C->A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine.[J]. Br J Clin Pharmacol,1999,47(4):445-449.
[68]Huang M, Han Y, Zhang X, et al. An intron polymorphism in the CXCL16 gene is associated with increased risk of coronary artery disease in Chinese Han population:A large angiography-based study.[J]. Atherosclerosis,2009.
[1]Yong RY, Chee CK, Yap EP. A two-stage approach identifies a Q344X mutation in the rhodopsin gene of a Chinese Singaporean family with autosomal dominant retinitis pigmentosa[J]. Ann Acad Med Singapore,2005, 34(1):94-99
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