一个新的视网膜色素变性的连锁位点RP33，以及RP11连锁家系中PRPF31基因完整突变筛查
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摘要
一个新的视网膜色素变性的连锁位点RP33，以及RP11连锁家系中PRPF31基因的完整突变筛查
研究目的：
分析两个常染色体显性视网膜色素变性(autosomal dominant retinitis pigmentosa，adRP)家系AA、AB的临床表型特征并研究其遗传学病因。通过全基因组连锁分析首先进行家系疾病的遗传学定位，然后在连锁区内进行候选基因突变筛查。
1．研究两个adRP家系AA、AB的临床表型特征。
2．通过全基因组扫描连锁分析确定两个adRP家系致病基因的染色体定位。
3．通过基因序列分析对连锁区内一系列可能的候选基因进行突变筛查，寻找致病基因。
4．通过新技术多重连接依赖探针扩增(Mutiplex Ligation-Dependent Probe Amplication，MLPA)反应和单核苷酸多态性(Single nucleotide polymorphism，SNPs)检测对RP11连锁家系AB进行候选基因PRPF31基因巨大缺失突变筛查。
研究方法：
1．临床研究方法：
1．1眼科常规检查
包括询问病史，屈光状态、眼前节裂隙灯检查，直接和间接眼底镜检查以及眼底照相等。
1．2特殊检查方法
包括视野检查(Humphrey 750)，明、暗适应视网膜电图(electroretinogram，ERG)以及多焦视网膜电图(multifocal ERG)检查等。
2．分子遗传学研究方法：
2．1取家系成员外周静脉血5～8ml，采用Roche Biochemical公司的DNA分离试剂盒提取基因组DNA。
2．2遗传连锁分析
2．2．1全基因组扫描连锁分析
在全部常染色体范围内选取370对荧光微卫星标记物进行全基因组扫描，相邻微卫星标记物之间的平均距离为10厘摩(Centimorgan，cM)。利用聚合酶链反应(Polymerase Chain Reaction，PCR)扩增全部370对荧光微卫星标记物。利用ABI 377XL DNA测序仪读取370对微卫星标记物等位基因片段大小并利用Genescan 3.1和Genotyper 2.0软件进行单体型分析。运用Sim Walk2 2.89，Version 3.35软件计算计算疾病表型与多个微卫星位点之间的多点最大优势对数LOD值。
2．2．2精确连锁定位
在通过全基因组连锁分析取得疾病基因在染色体上的初步定位以后，在取得最大正数LOD值的初步定位区域内进一步选取荧光标记微卫星标记物，以缩小并精确连锁区域临界范围。标记物之间的平均距离为1cM。
2．3基因序列分析
根据连锁分析的结果，分别在AA和AB两个家系所定位的染色体候选区内选取侯选基因，并用ABI 3730 Genetic Analyzer对侯选基因进行直接基因序列分析。
2．4 PRPF31基因的巨大突变筛查
在AB家系中对PRPF31基因进行SNPs和MLPA检测以筛查潜在的巨大基因缺失突变即基因半合子状态(hemizygousity)。
研究结果：
1．AA家系
临床上，AA家系中的患者以夜盲起病，发病年龄较晚，表现为进行性视力下降和周边视野缺损。RP临床表现在家系患者之间甚至同一患者的双眼之间均具有较大的变异，致病基因外显不全。
通过全基因组连锁分析在排除了所有已知adRP连锁位点之后，在2号染色体长臂上确定了一个新的adRP连锁位点RP33(OMIM％610395)。在微卫星标记物D2S2222取得最大多点LOD值4.69，通过家系中的两个正常同胞身上发生的重组(recombinant)可将RP33位点定位于微卫星标记D2S2159和D2S1343之间约4.8cM的区域(染色体带2cen-q12.1)内。
对RP33区域中的候选基因SEMA4C，CNGA3和HNK1ST以及紧邻RP33区域的一个已知arRP相关基因MERTK进行序列分析未发现任何致病突变。
2．AB家系
AB家系在临床上属弥漫型RP表型且具有较高外显率。此外，家系中有13名患者还同时具有皮质型白内障表型。
通过全基因组连锁分析和进一步的精确定位将此家系致病基因定位于染色体区19q13.4(RP11)(OMIM #600138)，微卫星标记物D19S924和D19S880之间约5.71cM区域内。
对连锁区内的已知adRP基因PRPF31进行完整的突变筛查基本排除了PRPF31全部阅读框架范围内的突变。进一步在连锁区域内选取其它候选基因PRKCG、TFPT、TSEN34、RDH13和U2AF2进行直接测序未发现致病性突变。
结论：
1．AA和AB家系属于常染色体显性遗传视网膜色素变性家系。
2．通过AA家系定位了一个新的adRP连锁位点RP33于染色体区域2cen-q12.1，这是首个由中国报道的RP新位点。SEMA4C、CNGA3、HNK1ST和MERTK基因均不是AA家系的致病基因，在RP33区域内存在的新adRP致病基因还有待发现。
3．AB家系连锁于染色体区域19q13.4(RP11位点)。RP11基因PRPF31不是AB家系的致病基因。在连锁区域19q13.4内，除了PRPF31基因之外，我们推测还存在另一个新的adRP相关致病基因导致了AB家系中弥漫型RP表现且可能还合并有外显不全的白内障表型。
RP33. a novel locus of autosomal dominant retinitis pigmentosa；and a complete mutation screening of PRPF31 gene in RP11 linked family
Objective
To study the clinical manifestations of two Chinese families with autosomal dominant retinitis pigmentosa(adRP)and investigate their genetic pathogenesis．A genome wide linkage analysis was applied and followed by a complete mutation screening of candidate genes．
1. To clinically characterize two families with adRP(kindred AA and AB)．
2. To identify the chromosomal locations of the disease loci in the two adRP families by genome-wide linkage screening．
3．To search the Causative mutation of cardidate genes within linked regions in the two families respectively．
4．To screen any substantial big deletion mutation in PRPF31 gene in family AB by mutiplex ligation-dependent probe amplication (MLPA) reaction and single nucleotide polymorphism(SNPs)testing．
Methods：
1. Clinical investigation
1.1 Routine ophthalmologic examinations
Ophthalmologic examinations including disease history, best correct visual acuity, slit-lamp examinations, direct funduscopy and photographphic fundus．
1.2 Electrophysiological examinations
Humphrey threshold perimetry (Humphrey 750), full field electroretinogram (ERG) and multifocal ERG (mfERG) were performed in all patients of the two families.
2. Molecular genetic study
2.1 Human genomic DNA was extracted from peripheral blood leukocytes using DNA Isolation Kits for Mammalian Blood (Roche Biochemical, Inc.).
2.2 Linkage analysis
2.2.1 Genome-wide linkage analysis
A genome-wide linkage screening was conducted by genotyping 370 microsatellite markers representing all autosomes at an average resolution of approximately 10 cM (Weberset 6.0; Research Genetics). The polymerase chain reactions (PCR) were carried out to amplify all 370 markers. The PCR products were appropriately pooled according to allele sizes and labelling, and were run in ABI 377XL for fluorescent detection. Linkage analyses were carried out by calculating multipoint LOD scores using the LINKAGE software package of SimWalk2 2.89, Version 3.35.
2.2.2 Fine mapping
Based upon the genome-wide linkage analysis, more fluorescent microsatellite markers located within the initial linked regions were genotyped to refine the critical interval.
2.3 Sequence analysis
Candidate genes were selected from linked regions of the two families respectively and direct sequencing was performed using ABI 3730 Genetic Analyzer to evaluate all the exons and flanking introns sequences of the candidate genes.
2.4 Detection for big deletion in PRPF31 gene
SNPs testing and MLPA reaction were applied in family AB to detect any substantial big deletions (hemizygousity) ofPRPF31 gene.
Result:
1. AA family
Clinically, AA family presented relatively late onset of night blindness, gradually decreased visual acuity and progressive loss of peripheral visual field. Variable clinical features and incomplete penetrance were found in the affected members of AA family.
After excluding all known adRP loci by genome-wide linkage analysis, a novel disease locus RP33 (OMIM %610395) was assigned to the long arm of chromosome
2. From meiotic recombinations in two unaffected members, RP33 was further refined to a 4.8 cM (9.5 Mb) interval flanked by D2S2159 and D2S1343 in chromosomal region 2cen-q12.1.
No disease-associated mutations were detected in the candidate genes SEMA4C,CNGA3 or HNKlST from within RP33 region. MERTK, a known disease gene for autosomal recessive RP located close to RP33 was similarly excluded.
2. AB family
AB family presented a form of diffuse adRP phenotype with high penetrance. In addition, cortex cataract was also observed in 13 affected members with adRP phenotype.
AdRP in family AB was mapped to chromosomal region 19q13.4 (RP11 locus, OMIM #600138) , a 5.71 cM interval flanked by microsatellite markers D19S924 and D19S880. A maximum multi-point LOD score of 7.46 was reached at marker D19S927.
After a relatively complete mutation screening throughout the open reading frame of PRPF31 gene, it has been excluded that the PRPF31 gene is the causative gene of AB family. No disease-associated mutations were detected in other candidate genes PRKCG, TFPT, TSEN34 or RDH13 from within the linked region. U2AF2, an essential pre-mRNA splicing factor coding gene located close to the critical interval was similar excluded.
Conclusions:
1. Pedigrees analysis demonstrated that the RP conditions in kindred AA and AB are both inherited as an autosomal dominant (adRP) trait.
2. A novel adRP locus RP33 (OMIM %610395) was assigned to chromosomal region 2cen-q12.1 in AA family. It's the first novel RP locus reported by China. SEMA4C, CNGA3, HNK1ST and MERTK genes are not the causative gene in AA family. There is a new gene in RP33 region which is responsible for adRP phenotype.
3. Family AB was linked to chromosomal region 19q13.4 (RP11 locus). PRPF31 gene is not the causative gene for the adRP phynotype in AB family. In addition to PRPF31, there may be a new adRP related gene in RP11 locus, which caused the diffuse form of adRP phenotype in AB family, or might be also causative for the cataract phenotype.
研究目的：
分析两个常染色体显性视网膜色素变性(autosomal dominant retinitis pigmentosa，adRP)家系AA、AB的临床表型特征并研究其遗传学病因。通过全基因组连锁分析首先进行家系疾病的遗传学定位，然后在连锁区内进行候选基因突变筛查。
1．研究两个adRP家系AA、AB的临床表型特征。
2．通过全基因组扫描连锁分析确定两个adRP家系致病基因的染色体定位。
3．通过基因序列分析对连锁区内一系列可能的候选基因进行突变筛查，寻找致病基因。
4．通过新技术多重连接依赖探针扩增(Mutiplex Ligation-Dependent Probe Amplication，MLPA)反应和单核苷酸多态性(Single nucleotide polymorphism，SNPs)检测对RP11连锁家系AB进行候选基因PRPF31基因巨大缺失突变筛查。
研究方法：
1．临床研究方法：
1．1眼科常规检查
包括询问病史，屈光状态、眼前节裂隙灯检查，直接和间接眼底镜检查以及眼底照相等。
1．2特殊检查方法
包括视野检查(Humphrey 750)，明、暗适应视网膜电图(electroretinogram，ERG)以及多焦视网膜电图(multifocal ERG)检查等。
2．分子遗传学研究方法：
2．1取家系成员外周静脉血5～8ml，采用Roche Biochemical公司的DNA分离试剂盒提取基因组DNA。
2．2遗传连锁分析
2．2．1全基因组扫描连锁分析
在全部常染色体范围内选取370对荧光微卫星标记物进行全基因组扫描，相邻微卫星标记物之间的平均距离为10厘摩(Centimorgan，cM)。利用聚合酶链反应(Polymerase Chain Reaction，PCR)扩增全部370对荧光微卫星标记物。利用ABI 377XL DNA测序仪读取370对微卫星标记物等位基因片段大小并利用Genescan 3.1和Genotyper 2.0软件进行单体型分析。运用Sim Walk2 2.89，Version 3.35软件计算计算疾病表型与多个微卫星位点之间的多点最大优势对数LOD值。
2．2．2精确连锁定位
在通过全基因组连锁分析取得疾病基因在染色体上的初步定位以后，在取得最大正数LOD值的初步定位区域内进一步选取荧光标记微卫星标记物，以缩小并精确连锁区域临界范围。标记物之间的平均距离为1cM。
2．3基因序列分析
根据连锁分析的结果，分别在AA和AB两个家系所定位的染色体候选区内选取侯选基因，并用ABI 3730 Genetic Analyzer对侯选基因进行直接基因序列分析。
2．4 PRPF31基因的巨大突变筛查
在AB家系中对PRPF31基因进行SNPs和MLPA检测以筛查潜在的巨大基因缺失突变即基因半合子状态(hemizygousity)。
研究结果：
1．AA家系
临床上，AA家系中的患者以夜盲起病，发病年龄较晚，表现为进行性视力下降和周边视野缺损。RP临床表现在家系患者之间甚至同一患者的双眼之间均具有较大的变异，致病基因外显不全。
通过全基因组连锁分析在排除了所有已知adRP连锁位点之后，在2号染色体长臂上确定了一个新的adRP连锁位点RP33(OMIM％610395)。在微卫星标记物D2S2222取得最大多点LOD值4.69，通过家系中的两个正常同胞身上发生的重组(recombinant)可将RP33位点定位于微卫星标记D2S2159和D2S1343之间约4.8cM的区域(染色体带2cen-q12.1)内。
对RP33区域中的候选基因SEMA4C，CNGA3和HNK1ST以及紧邻RP33区域的一个已知arRP相关基因MERTK进行序列分析未发现任何致病突变。
2．AB家系
AB家系在临床上属弥漫型RP表型且具有较高外显率。此外，家系中有13名患者还同时具有皮质型白内障表型。
通过全基因组连锁分析和进一步的精确定位将此家系致病基因定位于染色体区19q13.4(RP11)(OMIM #600138)，微卫星标记物D19S924和D19S880之间约5.71cM区域内。
对连锁区内的已知adRP基因PRPF31进行完整的突变筛查基本排除了PRPF31全部阅读框架范围内的突变。进一步在连锁区域内选取其它候选基因PRKCG、TFPT、TSEN34、RDH13和U2AF2进行直接测序未发现致病性突变。
结论：
1．AA和AB家系属于常染色体显性遗传视网膜色素变性家系。
2．通过AA家系定位了一个新的adRP连锁位点RP33于染色体区域2cen-q12.1，这是首个由中国报道的RP新位点。SEMA4C、CNGA3、HNK1ST和MERTK基因均不是AA家系的致病基因，在RP33区域内存在的新adRP致病基因还有待发现。
3．AB家系连锁于染色体区域19q13.4(RP11位点)。RP11基因PRPF31不是AB家系的致病基因。在连锁区域19q13.4内，除了PRPF31基因之外，我们推测还存在另一个新的adRP相关致病基因导致了AB家系中弥漫型RP表现且可能还合并有外显不全的白内障表型。
RP33. a novel locus of autosomal dominant retinitis pigmentosa；and a complete mutation screening of PRPF31 gene in RP11 linked family
Objective
To study the clinical manifestations of two Chinese families with autosomal dominant retinitis pigmentosa(adRP)and investigate their genetic pathogenesis．A genome wide linkage analysis was applied and followed by a complete mutation screening of candidate genes．
1. To clinically characterize two families with adRP(kindred AA and AB)．
2. To identify the chromosomal locations of the disease loci in the two adRP families by genome-wide linkage screening．
3．To search the Causative mutation of cardidate genes within linked regions in the two families respectively．
4．To screen any substantial big deletion mutation in PRPF31 gene in family AB by mutiplex ligation-dependent probe amplication (MLPA) reaction and single nucleotide polymorphism(SNPs)testing．
Methods：
1. Clinical investigation
1.1 Routine ophthalmologic examinations
Ophthalmologic examinations including disease history, best correct visual acuity, slit-lamp examinations, direct funduscopy and photographphic fundus．
1.2 Electrophysiological examinations
Humphrey threshold perimetry (Humphrey 750), full field electroretinogram (ERG) and multifocal ERG (mfERG) were performed in all patients of the two families.
2. Molecular genetic study
2.1 Human genomic DNA was extracted from peripheral blood leukocytes using DNA Isolation Kits for Mammalian Blood (Roche Biochemical, Inc.).
2.2 Linkage analysis
2.2.1 Genome-wide linkage analysis
A genome-wide linkage screening was conducted by genotyping 370 microsatellite markers representing all autosomes at an average resolution of approximately 10 cM (Weberset 6.0; Research Genetics). The polymerase chain reactions (PCR) were carried out to amplify all 370 markers. The PCR products were appropriately pooled according to allele sizes and labelling, and were run in ABI 377XL for fluorescent detection. Linkage analyses were carried out by calculating multipoint LOD scores using the LINKAGE software package of SimWalk2 2.89, Version 3.35.
2.2.2 Fine mapping
Based upon the genome-wide linkage analysis, more fluorescent microsatellite markers located within the initial linked regions were genotyped to refine the critical interval.
2.3 Sequence analysis
Candidate genes were selected from linked regions of the two families respectively and direct sequencing was performed using ABI 3730 Genetic Analyzer to evaluate all the exons and flanking introns sequences of the candidate genes.
2.4 Detection for big deletion in PRPF31 gene
SNPs testing and MLPA reaction were applied in family AB to detect any substantial big deletions (hemizygousity) ofPRPF31 gene.
Result:
1. AA family
Clinically, AA family presented relatively late onset of night blindness, gradually decreased visual acuity and progressive loss of peripheral visual field. Variable clinical features and incomplete penetrance were found in the affected members of AA family.
After excluding all known adRP loci by genome-wide linkage analysis, a novel disease locus RP33 (OMIM %610395) was assigned to the long arm of chromosome
2. From meiotic recombinations in two unaffected members, RP33 was further refined to a 4.8 cM (9.5 Mb) interval flanked by D2S2159 and D2S1343 in chromosomal region 2cen-q12.1.
No disease-associated mutations were detected in the candidate genes SEMA4C,CNGA3 or HNKlST from within RP33 region. MERTK, a known disease gene for autosomal recessive RP located close to RP33 was similarly excluded.
2. AB family
AB family presented a form of diffuse adRP phenotype with high penetrance. In addition, cortex cataract was also observed in 13 affected members with adRP phenotype.
AdRP in family AB was mapped to chromosomal region 19q13.4 (RP11 locus, OMIM #600138) , a 5.71 cM interval flanked by microsatellite markers D19S924 and D19S880. A maximum multi-point LOD score of 7.46 was reached at marker D19S927.
After a relatively complete mutation screening throughout the open reading frame of PRPF31 gene, it has been excluded that the PRPF31 gene is the causative gene of AB family. No disease-associated mutations were detected in other candidate genes PRKCG, TFPT, TSEN34 or RDH13 from within the linked region. U2AF2, an essential pre-mRNA splicing factor coding gene located close to the critical interval was similar excluded.
Conclusions:
1. Pedigrees analysis demonstrated that the RP conditions in kindred AA and AB are both inherited as an autosomal dominant (adRP) trait.
2. A novel adRP locus RP33 (OMIM %610395) was assigned to chromosomal region 2cen-q12.1 in AA family. It's the first novel RP locus reported by China. SEMA4C, CNGA3, HNK1ST and MERTK genes are not the causative gene in AA family. There is a new gene in RP33 region which is responsible for adRP phenotype.
3. Family AB was linked to chromosomal region 19q13.4 (RP11 locus). PRPF31 gene is not the causative gene for the adRP phynotype in AB family. In addition to PRPF31, there may be a new adRP related gene in RP11 locus, which caused the diffuse form of adRP phenotype in AB family, or might be also causative for the cataract phenotype.
引文
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23. Gusella JF, Wexler NS, Conneally PM, et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature 1983;306:234-238.
24. Jeffreys AJ, Wilson V, Thein SL. Hypervariable 'minisatellite' regions in human DNA. Nature 1985;314:67-73.
25. Nakamura Y, Leppert M, O'Connell P, et al. Variable number of tandem repeat (VNTR) markers for human gene mapping. Science 1987;235:1616-1622.
26. Saiki RK, Scharf S, Faloona F, et al. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 1985;230:1350-1354.
27. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science 2001;291:1304-1351.
28. Wang WY, Todd JA. The usefulness of different density SNP maps for disease association studies of common variants. Human molecular genetics 2003;12:3145-3149.
29. Martin ER, Gilbert JR, Lai EH, et al. Analysis of association at single nucleotide polymorphisms in the APOE region. Genomics 2000;63:7-12.
30. Lander ES, Schork NJ. Genetic dissection of complex traits. Science 1994;265:2037-2048.
31. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES. Parametric and nonparametric linkage analysis: a unified multipoint approach. American journal of human genetics 1996;58:1347-1363.
32. Kuwano A, Ledbetter SA, Dobyns WB, Emanuel BS, Ledbetter DH. Detection of deletions and cryptic translocations in Miller-Dieker syndrome by in situ hybridization. American journal of human genetics 1991;49:707-714.
33. Howley PM, Israel MA, Law MF, Martin MA. A rapid method for detecting and mapping homology between heterologous DNAs. Evaluation of polyomavirus genomes. The Journal of biological chemistry 1979;254:4876-4883.
34. Sellner LN, Taylor GR. MLPA and MAPH: new techniques for detection of gene deletions. Human mutation 2004;23:413-419.
35. Berson EL. Retinitis pigmentosa. The Friedenwald Lecture. Investigative ophthalmology & visual science 1993;34:1659-1676.
36. Gal A, Li Y, Thompson DA, et al. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nature genetics 2000;26:270-271.
37. Papaioannou M, Chakarova CF, Prescott DC, et al. A new locus (RP31) for autosomal dominant retinitis pigmentosa maps to chromosome 9p. Human genetics 2005;118:501-503.
38. Downey LM, Keen TJ, Jalili IK, et al. Identification of a locus on chromosome 2q11 at which recessive amelogenesis imperfecta and cone-rod dystrophy cosegregate. Eur J Hum Genet 2002;10:865-869.
39. Michaelides M, Bloch-Zupan A, Holder GE, Hunt DM, Moore AT. An autosomal recessive cone-rod dystrophy associated with amelogenesis imperfecta. Journal of medical genetics 2004;41:468-473.
40. Inagaki S, Furuyama T, Iwahashi Y. Identification of a member of mouse semaphorin family. FEBS letters 1995;370:269-272.
41. Abid A, Ismail M, Mehdi SQ, Khaliq S. Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases. Journal of medical genetics 2006;43:378-381.
42. Rice DS, Huang W, Jones HA, et al. Severe retinal degeneration associated with disruption of semaphorin 4A. Investigative ophthalmology & visual science 2004;45:2767-2777.
43. Kohl S, Marx T, Giddings I, et al. Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nature genetics 1998; 19:257-259.
44. Wissinger B, Gamer D, Jagle H, et al. CNGA3 mutations in hereditary cone photoreceptor disorders. American journal of human genetics 2001 ;69:722-737.
45. Wissinger B, Jagle H, Kohl S, et al. Human rod monochromacy: linkage analysis and mapping of a cone photoreceptor expressed candidate gene on chromosome 2qll. Genomics 1998;51:325-331.
46. Ong E, Yeh JC, Ding Y, et al. Structure and function of HNK-1 sulfotransferase. Identification of donor and acceptor binding sites by site-directed mutagenesis. The Journal of biological chemistry 1999;274 -.25608-25612.
47. Mitsumoto Y, Oka S, Sakuma H, Inazawa J, Kawasaki T. Cloning and chromosomal mapping of human glucuronyltransferase involved in biosynthesis of the HNK-1 carbohydrate epitope. Genomics 2000;65:166-173.
48. Uusitalo M, Schlotzer-Schrehardt U, Kivela T. Ultrastructural localization of the HNK-1 carbohydrate epitope to glial and neuronal cells of the human retina. Investigative ophthalmology & visual science 2003;44:961-964.
49. Laggerbauer B, Lauber J, Luhrmann R. Identification of an RNA-dependent ATPase activity in mammalian U5 snRNPs. Nucleic acids research 1996;24:868-875.
50. Lauber J, Fabrizio P, Teigelkamp S, Lane WS, Hartmann E, Luhrmann R. The HeLa 200 kDa U5 snRNP-specific protein and its homologue in Saccharomyces cerevisiae are members of the DEXH-box protein family of putative RNA helicases. The EMBO journal 1996; 15:4001-4015.
51. Stern RF, Roberts RG, Mann K, Yau SC, Berg J, Ogilvie CM. Multiplex ligation-dependent probe amplification using a completely synthetic probe set. BioTechniques 2004;37:399-405.
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53. McGee TL, Devoto M, Ott J, Berson EL, Dryja TP. Evidence that the penetrance of mutations at the RP11 locus causing dominant retinitis pigmentosa is influenced by a gene linked to the homologous RP11 allele. American journal of human genetics 1997;61:1059-1066.
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2. Rivolta C, Sharon D, DeAngelis MM, Dryja TP. Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns. Human molecular genetics 2002; 11:1219-1227.
3. van Soest S, Westerveld A, de Jong PT, Bleeker-Wagemakers EM, Bergen AA. Retinitis pigmentosa: defined from a molecular point of view. Survey of ophthalmology 1999;43:321-334.
4. van Lith-Verhoeven JJ, van der Velde-Visser SD, Sohocki MM, et al. Clinical characterization, linkage analysis, and PRPC8 mutation analysis of a family with autosomal dominant retinitis pigmentosa type 13 (RP13). Ophthalmic genetics 2002;23:l-12.
5. Al-Maghtheh M, Vithana E, Tarttelin E, et al. Evidence for a major retinitis pigmentosa locus on 19q13.4 (RP11) and association with a unique bimodal expressivity phenotype. American journal of human genetics 1996;59:864-871.
6. McGee TL, Devoto M, Ott J, Berson EL, Dryja TP. Evidence that the penetrance of mutations at the RP11 locus causing dominant retinitis pigmentosa is influenced by a gene linked to the homologous RP11 allele. American journal of human genetics 1997;61:1059-1066.
7. McWilliam P, Farrar GJ, Kenna P, et al. Autosomal dominant retinitis pigmentosa (ADRP): localization of an ADRP gene to the long arm of chromosome 3. Genomics 1989;5:619-622.
8. Dryja TP, McGee TL, Reichel E, et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 1990;343:364-366.
9. Zhao C, Lu S, Zhou X, Zhang X, Zhao K, Larsson C. A novel locus (RP33) for autosomal dominant retinitis pigmentosa mapping to chromosomal region 2cen-q12.1. Human genetics 2006;119:617-623.
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12. Vithana EN, Abu-Safieh L, Allen MJ, et al. A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19ql3.4 (RP11). Molecular cell 2001;8:375-381.
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15. Makarova OV, Makarov EM, Liu S, Vornlocher HP, Luhrmann R. 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. The EMBO journal 2002;21: 1148-1157.
16. al-Maghtheh M, Inglehearn CF, Keen TJ, et al. Identification of a sixth locus for autosomal dominant retinitis pigmentosa on chromosome 19. Human molecular genetics 1994;3:351-354.
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18. Vithana E, Al-Maghtheh M, Bhattacharya SS, Ingleheam CF. RP11 is the second most common locus for dominant retinitis pigmentosa. Journal of medical genetics 1998;35:174-175.
19. Chakarova CF, Cherninkova S, Tournev I, et al. Molecular genetics of retinitis pigmentosa in two Romani (Gypsy) families. Molecular vision 2006;12:909-914.
20. Lu SS, Zhao C, Cui Y, Li ND, Zhang XM, Zhao KX. [Novel splice-site mutation in the pre-mRNA splicing gene PRPF31 in a Chinese family with autosomal dominant retinitis pigmentosa]. [Zhonghua yan ke za zhi] Chinese journal of ophthalmology 2005;41:305-311.
21. Martinez-Gimeno M, Gamundi MJ, Hernan I, et al. Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa. Investigative ophthalmology & visual science 2003;44:2171-2177.
22. Sato H, Wada Y, Itabashi T, Nakamura M, Kawamura M, Tamai M. Mutations in the pre-mRNA splicing gene, PRPF31, in Japanese families with autosomal dominant retinitis pigmentosa. American journal of ophthalmology 2005;140:537-540.
23. Sullivan LS, Bowne SJ, Birch DG, et al. Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families. Investigative ophthalmology & visual science 2006;47:3052-3064.
24. 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. American journal of medical genetics 2003;121:235-239.
25. Xia K, Zheng D, Pan Q, et al. A novel PRPF31 splice-site mutation in a Chinese family with autosomal dominant retinitis pigmentosa. Molecular vision 2004; 10:361-365.
26. Wang DY, Chan WM, Tam PO, et al. Gene mutations in retinitis pigmentosa and their clinical implications. Clinica chimica acta; international journal of clinical chemistry 2005;351:5-16.
27. Sellner LN, Taylor GR. MLPA and MAPH: new techniques for detection of gene deletions. Human mutation 2004;23:413-419.
28. Sullivan LS, Bowne SJ, Seaman CR, et al. Genomic rearrangements of the PRPF31 gene account for 2.5% of autosomal dominant retinitis pigmentosa. Investigative ophthalmology & visual science 2006;47:4579-4588.
29. Abu-Safieh L, Vithana EN, Mantel I, et al. A large deletion in the adRP gene PRPF31: evidence that haploinsufficiency is the cause of disease. Molecular vision 2006;12:384-388.
30. Hamm HE, Bownds MD. Protein complement of rod outer segments of frog retina. Biochemistry 1986;25:4512-4523.
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32. Yuan L, Kawada M, Havlioglu N, Tang H, Wu JY. Mutations in PRPF31 inhibit pre-mRNA splicing of rhodopsin gene and cause apoptosis of retinal cells. J Neurosci 2005; 25: 748-757.
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2. Pang CP, Lam DS. Differential occurrence of mutations causative of eye diseases in the Chinese population. Human mutation 2002; 19:189-208.
3. Wang Q, Chen Q, Zhao K, Wang L, Wang L, Traboulsi EI. Update on the molecular genetics of retinitis pigmentosa. Ophthalmic genetics 2001;22:133-154.
4. van Soest S, Westerveld A, de Jong PT, Bleeker-Wagemakers EM, Bergen AA. Retinitis pigmentosa: defined from a molecular point of view. Survey of ophthalmology 1999;43:321-334.
5. Bird AC. Retinal photoreceptor dystrophies LI. Edward Jackson Memorial Lecture. American journal of ophthalmology 1995;119:543-562.
6. van Lith-Verhoeven JJ, van der Velde-Visser SD, Sohocki MM, et al. Clinical characterization, linkage analysis, and PRPC8 mutation analysis of a family with autosomal dominant retinitis pigmentosa type 13 (RP13). Ophthalmic genetics 2002;23:l-12.
7. Rivolta C, Sharon D, DeAngelis MM, Dryja TP. Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns. Human molecular genetics 2002;11:1219-1227.
8. McWilliam P, Farrar GJ, Kenna P, et al. Autosomal dominant retinitis pigmentosa (ADRP): localization of an ADRP gene to the long arm of chromosome 3. Genomics 1989;5:619-622.
9. Dryja TP, McGee TL, Reichel E, et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 1990;343:364-366.
10. Zhao C, Lu S, Zhou X, Zhang X, Zhao K, Larsson C. A novel locus (RP33) for autosomal dominant retinitis pigmentosa mapping to chromosomal region 2cen-q12.1. Human genetics 2006;119:617-623.
11. Daiger SP. Identifying retinal disease genes: how far have we come, how far do we have to go? Novartis Foundation symposium 2004;255:17-27; discussion 27-36, 177-178.
12. Hims MM, Diager SP, Inglehearn CF. Retinitis pigmentosa: genes, proteins and prospects. Developments in ophthalmology 2003;37:109-125.
13. Ahmed ZM, Riazuddin S, Riazuddin S, Wilcox ER. The molecular genetics of Usher syndrome. Clinical genetics 2003;63:431-444.
14. Koenig R. Bardet-Biedl syndrome and Usher syndrome. Developments in ophthalmology 2003 ;37:126-140.
15. Wang DY, Chan WM, Tam PO, et al. Gene mutations in retinitis pigmentosa and their clinical implications. Clinica chimica acta; international journal of clinical chemistry 2005;351:5-16.
16. Sullivan LS, Bowne SJ, Seaman CR, et al. Genomic rearrangements of the PRPF31 gene account for 2.5% of autosomal dominant retinitis pigmentosa. Investigative ophthalmology & visual science 2006;47:4579-4588.
17. Botstein D, White RL, Skolnick M, Davis RW. Construction of a genetic linkage map in man using restriction fragment length polymorphisms. American journal of human genetics 1980;32:314-331.
18. Botstein D, Risch N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nature genetics 2003;33 Suppl:228-237.
19. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature 2001;409:860-921.
20. Murray JC, Buetow KH, Weber JL, et al. A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC). Science 1994;265:2049-2054.
21. Immer FR. Calculating Linkage Intensities from F(3) Data. Genetics 1934;19:119-136.
22. Morton NE. Sequential tests for the detection of linkage. American journal of human genetics 1955;7:277-318.
23. Gusella JF, Wexler NS, Conneally PM, et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature 1983;306:234-238.
24. Jeffreys AJ, Wilson V, Thein SL. Hypervariable 'minisatellite' regions in human DNA. Nature 1985;314:67-73.
25. Nakamura Y, Leppert M, O'Connell P, et al. Variable number of tandem repeat (VNTR) markers for human gene mapping. Science 1987;235:1616-1622.
26. Saiki RK, Scharf S, Faloona F, et al. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 1985;230:1350-1354.
27. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science 2001;291:1304-1351.
28. Wang WY, Todd JA. The usefulness of different density SNP maps for disease association studies of common variants. Human molecular genetics 2003;12:3145-3149.
29. Martin ER, Gilbert JR, Lai EH, et al. Analysis of association at single nucleotide polymorphisms in the APOE region. Genomics 2000;63:7-12.
30. Lander ES, Schork NJ. Genetic dissection of complex traits. Science 1994;265:2037-2048.
31. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES. Parametric and nonparametric linkage analysis: a unified multipoint approach. American journal of human genetics 1996;58:1347-1363.
32. Kuwano A, Ledbetter SA, Dobyns WB, Emanuel BS, Ledbetter DH. Detection of deletions and cryptic translocations in Miller-Dieker syndrome by in situ hybridization. American journal of human genetics 1991;49:707-714.
33. Howley PM, Israel MA, Law MF, Martin MA. A rapid method for detecting and mapping homology between heterologous DNAs. Evaluation of polyomavirus genomes. The Journal of biological chemistry 1979;254:4876-4883.
34. Sellner LN, Taylor GR. MLPA and MAPH: new techniques for detection of gene deletions. Human mutation 2004;23:413-419.
35. Berson EL. Retinitis pigmentosa. The Friedenwald Lecture. Investigative ophthalmology & visual science 1993;34:1659-1676.
36. Gal A, Li Y, Thompson DA, et al. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nature genetics 2000;26:270-271.
37. Papaioannou M, Chakarova CF, Prescott DC, et al. A new locus (RP31) for autosomal dominant retinitis pigmentosa maps to chromosome 9p. Human genetics 2005;118:501-503.
38. Downey LM, Keen TJ, Jalili IK, et al. Identification of a locus on chromosome 2q11 at which recessive amelogenesis imperfecta and cone-rod dystrophy cosegregate. Eur J Hum Genet 2002;10:865-869.
39. Michaelides M, Bloch-Zupan A, Holder GE, Hunt DM, Moore AT. An autosomal recessive cone-rod dystrophy associated with amelogenesis imperfecta. Journal of medical genetics 2004;41:468-473.
40. Inagaki S, Furuyama T, Iwahashi Y. Identification of a member of mouse semaphorin family. FEBS letters 1995;370:269-272.
41. Abid A, Ismail M, Mehdi SQ, Khaliq S. Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases. Journal of medical genetics 2006;43:378-381.
42. Rice DS, Huang W, Jones HA, et al. Severe retinal degeneration associated with disruption of semaphorin 4A. Investigative ophthalmology & visual science 2004;45:2767-2777.
43. Kohl S, Marx T, Giddings I, et al. Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nature genetics 1998; 19:257-259.
44. Wissinger B, Gamer D, Jagle H, et al. CNGA3 mutations in hereditary cone photoreceptor disorders. American journal of human genetics 2001 ;69:722-737.
45. Wissinger B, Jagle H, Kohl S, et al. Human rod monochromacy: linkage analysis and mapping of a cone photoreceptor expressed candidate gene on chromosome 2qll. Genomics 1998;51:325-331.
46. Ong E, Yeh JC, Ding Y, et al. Structure and function of HNK-1 sulfotransferase. Identification of donor and acceptor binding sites by site-directed mutagenesis. The Journal of biological chemistry 1999;274 -.25608-25612.
47. Mitsumoto Y, Oka S, Sakuma H, Inazawa J, Kawasaki T. Cloning and chromosomal mapping of human glucuronyltransferase involved in biosynthesis of the HNK-1 carbohydrate epitope. Genomics 2000;65:166-173.
48. Uusitalo M, Schlotzer-Schrehardt U, Kivela T. Ultrastructural localization of the HNK-1 carbohydrate epitope to glial and neuronal cells of the human retina. Investigative ophthalmology & visual science 2003;44:961-964.
49. Laggerbauer B, Lauber J, Luhrmann R. Identification of an RNA-dependent ATPase activity in mammalian U5 snRNPs. Nucleic acids research 1996;24:868-875.
50. Lauber J, Fabrizio P, Teigelkamp S, Lane WS, Hartmann E, Luhrmann R. The HeLa 200 kDa U5 snRNP-specific protein and its homologue in Saccharomyces cerevisiae are members of the DEXH-box protein family of putative RNA helicases. The EMBO journal 1996; 15:4001-4015.
51. Stern RF, Roberts RG, Mann K, Yau SC, Berg J, Ogilvie CM. Multiplex ligation-dependent probe amplification using a completely synthetic probe set. BioTechniques 2004;37:399-405.
52. Al-Maghtheh M, Vithana E, Tarttelin E, et al. Evidence for a major retinitis pigmentosa locus on 19ql3.4 (RP11) and association with a unique bimodal expressivity phenotype. American journal of human genetics 1996;59:864-871.
53. McGee TL, Devoto M, Ott J, Berson EL, Dryja TP. Evidence that the penetrance of mutations at the RP11 locus causing dominant retinitis pigmentosa is influenced by a gene linked to the homologous RP11 allele. American journal of human genetics 1997;61:1059-1066.
54. Vithana EN, Abu-Safieh L, Pelosini L, et al. Expression of PRPF31 mRNA in patients with autosomal dominant retinitis pigmentosa: a molecular clue for incomplete penetrance? Investigative ophthalmology & visual science 2003;44:4204-4209.
55. al-Maghtheh M, Inglehearn CF, Keen TJ, et al. Identification of a sixth locus for autosomal dominant retinitis pigmentosa on chromosome 19. Human molecular genetics 1994;3:351-354.
56. Vithana EN, Abu-Safieh L, Allen MJ, et al. A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19ql3.4 (RP11). Molecular cell 2001;8:375-381.
57. Al-Maghtheh M, Vithana EN, Inglehearn CF, Moore T, Bird AC, Bhattacharya SS. Segregation of a PRKCG mutation in two RP11 families. American journal of human genetics 1998;62:1248-1252.
58. Hastings ML, Krainer AR. Pre-mRNA splicing in the new millennium. Current opinion in cell biology 2001;13:302-309.
59. Makarova OV, Makarov EM, Liu S, Vornlocher HP, Luhrmann R. 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. The EMBO journal 2002; 21: 1148-1157.
60. Chakarova CF, Cherninkova S, Tournev I, et al. Molecular genetics of retinitis pigmentosa in two Romani (Gypsy) families. Molecular vision 2006; 12: 909-914.
61. Lu SS, Zhao C, Cui Y, Li ND, Zhang XM, Zhao KX. [Novel splice-site mutation in the pre-mRNA splicing gene PRPF31 in a Chinese family with autosomal dominant retinitis pigmentosa]. [Zhonghua yan ke za zhi] Chinese journal of ophthalmology 2005; 41: 305-311.
62. Martinez-Gimeno M, Gamundi MJ, Hernan I, et al. Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa. Investigative ophthalmology & visual science 2003; 44: 2171-2177.
63. Sato H, Wada Y, Itabashi T, Nakamura M, Kawamura M, Tamai M. Mutations in the pre-mRNA splicing gene, PRPF31, in Japanese families with autosomal dominant retinitis pigmentosa. American journal of ophthalmology 2005; 140: 537-540.
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