原发性视网膜色素变性家系和Usher综合征家系临床表型分析及致病基因研究
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摘要
目的:
1.建立视网膜色素变性遗传资源收集保存的标准化操作程序。
2.分析3个RP家系RP-GC-001、RP-DX-002、RP-PG-003临床表型及遗传学特点,寻找致病基因突变。
3.分析2个Usher综合征家系USH-001、USH-002的临床表型特征及遗传学特点,筛选可能的已知致病基因位点。
方法:
1.对RP患者进行鉴定和临床分型,分析其遗传方式。收集、保存RP遗传资源,包括患者及家属的知情同意、填写RP调查表、抽取外周静脉血制备基因组DNA的、提取基因组DNA、保存及鉴定基因组DNA。建立RP遗传资源库,包括纸质档案管理系统和电子档案管理系统。
2.分析RP-GC-001、RP-DX-002、RP-PG-003家系患者的临床表型特征、系谱特征,利用PCR扩增和直接测序的方法并对RHO、RDS、ROM1、NRL、CRX等5个已知致病基因的15个外显子进行筛查。
3.分析USH-001、USH-002家系患者的临床表型特征、系谱特征,利用连锁分析的原理和方法,对12个已知致病基因位点周围的微卫星标记进行扫描,筛选可能的致病基因位点。
结果:
1.建立了规范、科学、合理,并且符合国际、国内遗传资源采集研究原则要求的视网膜色素变性遗传资源收集保存标准化操作系统。
2.RP-GC-001、RP-PG-002、RP-DX-003表型具有共性:夜盲、进行性视野缩小、视网膜骨细胞状色素沉着、视乳头呈蜡黄色萎缩,表型垂直连续传递,男女均可发病。同时又具个性特征:RP-DX-002家系中患者视网膜骨细胞样色素沉着累及黄斑区和视乳头旁,多个患者伴有虹膜局限性前粘连、玻璃体烟灰样混浊。RP-PG-003家系患者在50岁左右出现急性闭角型青光眼。RP-GC-001家系中发现了RHO基因外显子2编码区403C＞T Arg135Trp R135W突变。RP-PG-002、RP-DX-003家系的RHO、RDS、ROM1、NRL、CRX基因未发现致病突变
3.USH-001、USH-002家系均表现为儿童期出现的双耳听力下降,为非渐进性、中-重度感音神经性耳聋,以高频听力损失为主,前庭功能正常。10-13岁出现夜盲症状,随年龄增长夜盲逐渐加重,并出现视野逐渐缩窄至管状视野,中心视力下降不明显,临床表现符合USH2型。表型未出现连续遗传的现象,男女均有发病,患者的子女表型正常。USH-001家系中所有患者的D11S902、D17S785微卫星标记的Allele值完全一致,USH-002家系所有患者的微卫星标记D1S425、D9S1776的Allele值完全一致。
结论:
1.视网膜色素变性遗传资源收集保存标准化操作系统的建立,确保了本研究的规范性、保证了遗传资源搜集工作良好的延续性以及我们后续基因定位克隆、分子流行病学研究、基因筛查工作结果的真实可靠。
2.RP-GC-001、RP-PG-002、RP-DX-003为常染色体显性遗传RP家系。RHO基因外显子2编码区403C＞T Arg135Trp R135W突变为RP-GC-001家系的致病突变。RHO、RDS、ROM1、NRL和CRX不是RP-PG-002、RP-DX-003家系的致病基因。
3.USH-001、USH-002家系为USH2型家系,遗传方式为常染色体隐性遗传。USH1C、USH1G可能为USH-001家系的致病基因:USH2A、USH2D可能为USH-002家系的致病基因。
Objective:
1. To establish the standard system to collect and preserve the genetic resources of retinitis pigmentosa.
2. To analyze the clinical and genetic features of the three retinitis pigmentosa families: RP-GC-001 RP-DX-002 RP-PG-003, and to find pathogenic genes for the families.
3. To analyze the clinical features of the two Usher Syndrome families: USH-001 USH-002, and to find possible relevant USH gene map locus.
Methods:
1. RP patients were identified and classified, and their genetic patterns were analyzed. Collecting and preserving RP genetic resources including signing the informed consent, filling out RP questionnaire, extracting genomic DNA from peripheral blood, identification and preservation genomic DNA. Establishing RP genetic resources system including paper-based records management system and electronic records management system.
2. Analysis of the clinical and pedigree features of RP-GC-001 RP-DX-002 RP-PG-003 families. And detecting the 15 exons of the five known pathogenic genes: RHO, RDS, ROM1, NRL and CRX by PCR and direct sequencing.
3. Analysis of the clinical and pedigree features of USH-001 USH-002 families. And screening the short tandem repeat markers around the 12 known USH gene map locus to choose the possible relevant genes by use of the principles and methods of linkage analysis.
Results:
1. The system of collecting and preserving genetic resources of RP was standard scientific and reasonable. And it was in line with the international and domestic requirements and principles of genetic resources collection.
2. The common phenotype of the families RP-GC-001 P-PG-002 and RP-DX-003 were night blindness, narrowing of vision, bone cell-like retinal pigmentation, shrink of papilla of optic nerve. The phenotype vertically transmitted and appeared in both male and female patients. However, RP-DX-002 family had some characteristics: bone cell-like retinal pigmentation involved in macular and environment of papilla of optic nerve, many patients were with iris adhesion and soot-like vitreous opacity. And patients in RP-PG-003 family would have acute angle-closure glaucoma in their fifties. RHO exon 2 coding region of 403 C>T Argl35Trp R135W mutation was found in the RP-GC-001 familiy, and no pathogenic mutations of RHO RDS ROM1 CRX and NRL were found in the RP-PG-002 and RP-DX-003 families.
3. The phenotypes of the family USH-001 were similar to family USH-002: hearing loss in both ears in childhood, non-progressive sensorineural hearing loss, high-frequency hearing loss and normal vestibular function. Night blindness occurred in 10-13 years old and gradually got worse with age, visual field gradually narrowed to tubular vision, while the decline of visual acuity were not obvious. Their clinical manifestations were consistent with the diagnosis of USH2. The phenotype did not consecutively transmitte and appeared in both male and female patients. And patients in these two families all had normal children. In USH-001 family all the patients shared the same Allele of D11S902 and D17S785 short tandem repeat markers, and all the patients in USH-002 family shared the same Allele of D1S425and D9S1776 markers.
Conclusion:
1. Establishment of the system to preserve and collect RP genetic resources have ensured this study was standardized and had good continuity. It would make our follow-up results of positional cloning, molecular epidemiological study and genetic screening true and reliable.
2. The three RP families were autosomal dominant RP families. The mutation of RHO exon 2 coding region of 403 C>T Argl35Trp R135W was pathogenic mutation in RP-GC-001 family. RHO, RDS, ROM1, CRX and NRL were not the pathogenic genes for RP-PG-002 family and RP-DX-003 family.
3. USH-001 and USH-002 were USH2 families and their genetic forms were autosomal recessive. USHIC and USH1G were likely pathogenic genes for USH-001 family, USH2A and USH2D were likely pathogenic genes for USH-002 family.
1.建立视网膜色素变性遗传资源收集保存的标准化操作程序。
2.分析3个RP家系RP-GC-001、RP-DX-002、RP-PG-003临床表型及遗传学特点,寻找致病基因突变。
3.分析2个Usher综合征家系USH-001、USH-002的临床表型特征及遗传学特点,筛选可能的已知致病基因位点。
方法:
1.对RP患者进行鉴定和临床分型,分析其遗传方式。收集、保存RP遗传资源,包括患者及家属的知情同意、填写RP调查表、抽取外周静脉血制备基因组DNA的、提取基因组DNA、保存及鉴定基因组DNA。建立RP遗传资源库,包括纸质档案管理系统和电子档案管理系统。
2.分析RP-GC-001、RP-DX-002、RP-PG-003家系患者的临床表型特征、系谱特征,利用PCR扩增和直接测序的方法并对RHO、RDS、ROM1、NRL、CRX等5个已知致病基因的15个外显子进行筛查。
3.分析USH-001、USH-002家系患者的临床表型特征、系谱特征,利用连锁分析的原理和方法,对12个已知致病基因位点周围的微卫星标记进行扫描,筛选可能的致病基因位点。
结果:
1.建立了规范、科学、合理,并且符合国际、国内遗传资源采集研究原则要求的视网膜色素变性遗传资源收集保存标准化操作系统。
2.RP-GC-001、RP-PG-002、RP-DX-003表型具有共性:夜盲、进行性视野缩小、视网膜骨细胞状色素沉着、视乳头呈蜡黄色萎缩,表型垂直连续传递,男女均可发病。同时又具个性特征:RP-DX-002家系中患者视网膜骨细胞样色素沉着累及黄斑区和视乳头旁,多个患者伴有虹膜局限性前粘连、玻璃体烟灰样混浊。RP-PG-003家系患者在50岁左右出现急性闭角型青光眼。RP-GC-001家系中发现了RHO基因外显子2编码区403C＞T Arg135Trp R135W突变。RP-PG-002、RP-DX-003家系的RHO、RDS、ROM1、NRL、CRX基因未发现致病突变
3.USH-001、USH-002家系均表现为儿童期出现的双耳听力下降,为非渐进性、中-重度感音神经性耳聋,以高频听力损失为主,前庭功能正常。10-13岁出现夜盲症状,随年龄增长夜盲逐渐加重,并出现视野逐渐缩窄至管状视野,中心视力下降不明显,临床表现符合USH2型。表型未出现连续遗传的现象,男女均有发病,患者的子女表型正常。USH-001家系中所有患者的D11S902、D17S785微卫星标记的Allele值完全一致,USH-002家系所有患者的微卫星标记D1S425、D9S1776的Allele值完全一致。
结论:
1.视网膜色素变性遗传资源收集保存标准化操作系统的建立,确保了本研究的规范性、保证了遗传资源搜集工作良好的延续性以及我们后续基因定位克隆、分子流行病学研究、基因筛查工作结果的真实可靠。
2.RP-GC-001、RP-PG-002、RP-DX-003为常染色体显性遗传RP家系。RHO基因外显子2编码区403C＞T Arg135Trp R135W突变为RP-GC-001家系的致病突变。RHO、RDS、ROM1、NRL和CRX不是RP-PG-002、RP-DX-003家系的致病基因。
3.USH-001、USH-002家系为USH2型家系,遗传方式为常染色体隐性遗传。USH1C、USH1G可能为USH-001家系的致病基因:USH2A、USH2D可能为USH-002家系的致病基因。
Objective:
1. To establish the standard system to collect and preserve the genetic resources of retinitis pigmentosa.
2. To analyze the clinical and genetic features of the three retinitis pigmentosa families: RP-GC-001 RP-DX-002 RP-PG-003, and to find pathogenic genes for the families.
3. To analyze the clinical features of the two Usher Syndrome families: USH-001 USH-002, and to find possible relevant USH gene map locus.
Methods:
1. RP patients were identified and classified, and their genetic patterns were analyzed. Collecting and preserving RP genetic resources including signing the informed consent, filling out RP questionnaire, extracting genomic DNA from peripheral blood, identification and preservation genomic DNA. Establishing RP genetic resources system including paper-based records management system and electronic records management system.
2. Analysis of the clinical and pedigree features of RP-GC-001 RP-DX-002 RP-PG-003 families. And detecting the 15 exons of the five known pathogenic genes: RHO, RDS, ROM1, NRL and CRX by PCR and direct sequencing.
3. Analysis of the clinical and pedigree features of USH-001 USH-002 families. And screening the short tandem repeat markers around the 12 known USH gene map locus to choose the possible relevant genes by use of the principles and methods of linkage analysis.
Results:
1. The system of collecting and preserving genetic resources of RP was standard scientific and reasonable. And it was in line with the international and domestic requirements and principles of genetic resources collection.
2. The common phenotype of the families RP-GC-001 P-PG-002 and RP-DX-003 were night blindness, narrowing of vision, bone cell-like retinal pigmentation, shrink of papilla of optic nerve. The phenotype vertically transmitted and appeared in both male and female patients. However, RP-DX-002 family had some characteristics: bone cell-like retinal pigmentation involved in macular and environment of papilla of optic nerve, many patients were with iris adhesion and soot-like vitreous opacity. And patients in RP-PG-003 family would have acute angle-closure glaucoma in their fifties. RHO exon 2 coding region of 403 C>T Argl35Trp R135W mutation was found in the RP-GC-001 familiy, and no pathogenic mutations of RHO RDS ROM1 CRX and NRL were found in the RP-PG-002 and RP-DX-003 families.
3. The phenotypes of the family USH-001 were similar to family USH-002: hearing loss in both ears in childhood, non-progressive sensorineural hearing loss, high-frequency hearing loss and normal vestibular function. Night blindness occurred in 10-13 years old and gradually got worse with age, visual field gradually narrowed to tubular vision, while the decline of visual acuity were not obvious. Their clinical manifestations were consistent with the diagnosis of USH2. The phenotype did not consecutively transmitte and appeared in both male and female patients. And patients in these two families all had normal children. In USH-001 family all the patients shared the same Allele of D11S902 and D17S785 short tandem repeat markers, and all the patients in USH-002 family shared the same Allele of D1S425and D9S1776 markers.
Conclusion:
1. Establishment of the system to preserve and collect RP genetic resources have ensured this study was standardized and had good continuity. It would make our follow-up results of positional cloning, molecular epidemiological study and genetic screening true and reliable.
2. The three RP families were autosomal dominant RP families. The mutation of RHO exon 2 coding region of 403 C>T Argl35Trp R135W was pathogenic mutation in RP-GC-001 family. RHO, RDS, ROM1, CRX and NRL were not the pathogenic genes for RP-PG-002 family and RP-DX-003 family.
3. USH-001 and USH-002 were USH2 families and their genetic forms were autosomal recessive. USHIC and USH1G were likely pathogenic genes for USH-001 family, USH2A and USH2D were likely pathogenic genes for USH-002 family.
引文
1.Rivolta C,Sharon D,DeAngelisMM,et al.Retinitis pigmentosa and allied diseases:numerous diseases,genes,and inheritance patterns.Hum Mol Genet.2002,11(10):1219-27.
2.杨培增,陈家祺,葛坚,吴德正主编.眼科学基础与临床.北京:人民卫生出版社,2006,758-760.
3.Moller CG,Kimberling WJ,Davenport SL,et al.Usher syndrome:Anotoneurologic study.Laryngerscope.1989,99(1):73-9.
4.Boughman JA,Vernon M,shaver KA.Usher syndrome:definition and estimate of prevalence from two high-risk populations.J Chronic Dis.1983,36(8):595-603.
5.Kajiwara K,Berson EL,Dryja TP.Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci.Science.1994,264(5165):1604-8.
6.Pagon RA.Syndromic retinal dystrophy.Liviana Medicina.1993:pp.151-166.
7.李凤鸣主编.眼科全书.北京:人民卫生出版社,1999,624-701
8.Berson EL.Retinitis pigmentosa.Invest Ophthalmol Vis Sci.1993,34(5):1659-76.
9.Smith RJ,Berlin CI,Hejtmancik JF,et al.Clinical diagnosis of the Usher syndromes.Usher Syndrome Consortium.Am J Med Genet.1994,50(1):32-8.
10.《世界人类基因组与人权宣言》.联合国教科文组织第29届大会.巴梨黎.1997年11月11日.
11.《人类遗传资源管理暂行办法》.科技部、卫生部联合制定.北京.1998年6月.
12.RetNe http://www.sciencedirect.com/science?ob=RedirectURL&_method=ex ternObjhink&_locator=url&_cdi:4995&_plusSign=%2B&_targetURL=htt p%253A%252F%252Fwww.sph.uth.tmc.edu%252FRetNet%252F
13.van Soest S,Westerveld A,de Jong PT,et al.Retinitis pigmentosa:defined from a molecular point of view.Surv Ophthalmol.1999,43(4):321-34.
14.《赫尔辛基宣言》.第52届世界医学大会.苏格兰爱丁堡.2000年10月.
1.Travis GH.Mechanisms of cell death in the inherited retinal degenerations.Am J Hum Genet.1998,62(3):503-508.
2.Zack DJ.Birth and death in the retina:more related than we thought?Neuron.1999,23(3):549-55?.
3.Rimoin DL,Connor M,Pyeritz RE,et al.Hereditary retinal and choroidal degenerations.Edition(4th ed).New York.Churchill Living Stone.2002,3555-3593.
4.Pagon RA.Syndromic retinal dystrophy.Naples.Liviana Medicina.1993,151-166.
5. Nathans J, Hogness DS. Isolation and nucleotide sequence of the gene encoding human rhodopsin. Proc Natl Acad Sci USA. 1984, 81(15): 4851-5.
6. Andres A, GarrigaP, Manyosa J. Altered functionality in rhodopsin point mutants associated with retinitis pigmentosa. Biochem Biophys Res Commun. 2003, 303(1):294-301.
7. Sung CH, Davenport CM, Nathans J. Rhodopsin mutations responsible for autosomal dominant retinitis pigmentosa. Clustering of functional classes along the polypeptide chain. J Biol Chem. 1993, 268(35): 26645-49.
8. Roof DJ, Adamian M, Hayes A. Rhodopsin accumulation at abnormal sites in retinas of mice with a human P23H rhodopsin transgene . Invest Ophthalmol Vis Sci. 1994, 35(12):4049-62.
9. Roof DJ, Adamian M, Hayes A. Rhodopsin accumulation at abnormal sites in retinas of mice with a human P23H rhodopsin transgene . Invest Ophthalmol Vis Sci. 1994, 35(12):4049-62.
10. Bayés M, Martínez-Mir A, Valverde D, et al. Autosomal recessive retinitis pigmentosa in Spain: evaluation of four genes and two loci involved in the disease. Clin Genet. 1996, 50(5):380-7.
11. Sung CH, Davenport CM, Hennessey JC, et al. Rhodopsin mutations in autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A. 1991, 88(15): 6481-5.
12. Pannarale MR, Grammatico B, Iannaccone A, et al. Autosomal-dominant retinitis pigmentosa associated with an Arg-135-Trp point mutation of the rhodopsin gene. Clinical features and longitudinal observations. Ophthalmology. 1996, 103(9):1443-52.
13. Souied E, Soubrane G, Benlian P. et al. Retinitis punctata albescens associated with the Argl35Trp mutation in the rhodopsin gene. Am J Ophthalmol. 1996, 121(1):19-25.
14. Andreasson S, Ehinger B, Abrahamson M, et al. A six-generation family with autosomal dominant retinitis pigmentosa and a rhodopsin gene mutation (arginine-135-leucine). Ophthalmic Paediatr Genet. 1992, 13(3):145-53.
15. Min KC, Zvyaga TA, Cypess AM. Characterization of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. Mutations on the cytoplasmic surface affect transducin activation. J Biol Chem. 1993, 268(13):9400-4.
16. Travis GH, Christerson L, Danielson PE, et al. The human retinal degeneration slow (RDS) gene: chromosome assignment and structure of the mRNA. Genomics. 1991, 10(3): 733-9.
17. Travis GH, HeplerJE. A medley of retinal dystrophies. Nature Genet. 1993, 3(3): 191-2.
18. Nichols BE, Sheffield VC, Vandenburgh K, et al. Butterfly-shaped pigment dystrophy of the fovea caused by a point mutation in codon 167 of the RDS gene. Nature Genet. 1993, 3(3): 202-7.
19. Wroblewski JJ, Wells JA 3rd, Eckstein A, et al. Macular dystrophy associated with mutations at codon 172 in the human retinal degeneration slow gene. Ophthalmology. 1994, 101(1): 12-22.
20. Kohl S, Christ-Adler M, Apfelstedt-Sylla E, et al. RDS/peripherin gene mutations are frequent causes of central retinal dystrophies. J Med Genet. 1997, 34(8): 620-6.
21. Kajiwara K, Berson EL, Dryja TP. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROMl loci. Science. 1994, 264(5165):1604-8.
22. Nadeau JH. Modifier genes in mice and humans. Curr Opin Genet Dev. 2003, 13(3): 290-5.
23. Bascom RA, García-Heras J, Hsieh CL, et al. Localization of the photoreceptor gene ROMl to human chromosome 11 and mouse chromosome 19: sublocalization to human 11q13 between PGA and PYGM. Am J Hum Genet. 1992, 51(5):1028-35.
24. Bascom RA, Connell G, Garcia-Heras J, et al. Molecular and ultrastructural characterization of the products of the human retinopathy candidate genes R0M1 and RDS. Am J Hum Genet. 1990, 47 (suppl): A101.
25. Farjo Q, Jackson A, Pieke-Dahl S, et al. Human bZIP transcription factor gene NRL: structure, genomic sequence, and fine linkage mapping at 14qll. 2 and negative mutation analysis in patients with retinal degeneration. Genomics. 1997, 45(2):395-401.
26. Mitton KP, Swain PK, Khanna H, et al. Interaction of retinal bZIP transcription factor NRL with Flt3-interacting zinc-finger protein Fizl: possible role of Fizl as a transcriptional repressor. Hum Mol Genet. 2003, 12(4): 365-73.
27. Bessant DA, Holder GE, Fitzke FW, et al. Phenotype of retinitis pigmentosa associated with the ser50thr mutation in the NRL gene. Arch Ophthalmol. 2003, 121(6):793-802.
28. Furukawa T, Morrow EM, Cepko CL, et al. Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell. 1997, 91(4) :531-41.
29. Chen S, Wang QL, Xu S, et al. Functional analysis of cone-rod homeobox (CRX) mutations associated with retinal dystrophy. Hum Mol Genet. 2002, 11(8):873-84.
30. Rivolta C, Berson EL, Dryja TP. Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX. Hum Mutat. 2001, 18(6): 488-98.
1.Moller CG,Kimberling WJ,Davenport SLH,et al.Usher syndrome:Anotoneurologic study.Laryngerscope,1989,99:73-79.
2.Boughman JA,Vernon M,shaver KA,et al.Usher syndrome:definition and estimate of preverlence from two high-risk population.J Chronic Dis.1983,36:595-603.
3.Smith RJ,Berlin CI,Hejtmancik JF,et al.Clinical diagnostic of the Usher syndrome.Usher Syndrome Consortium.Am J Med Genet.1994,50:32-38.
4.Van Camp q Smith RJ.The Hereditary Hearing loss Homepage.http://webhost.ua.ac.be/hhh/.Lastupdated:February 16,2006.
5.Belal A.Usher's syndrome:a temporal bone report.J Iaryngol Otol,1975,89:175-181.
6.Shinkawa H,Nadol JB.Histopathology of the inner ear in Usher's syndrome as observed by light and electron microscopy.Ann Otol Rhinol Larygol,1986,95:313-317.
7.宋振英.Usher综合征.见:李凤鸣主编.眼科全书.北京:人民卫生出版社, 1996,3778-3779.
8.陈彭,赵明威,张承芬.视网膜色素变性.张承芬主编.眼底病学.北京:人民卫生出版社,1998,408-409.
9.Smith RJH,Berlin CI,Hejtmancik JF,et al.Clinical diagnosis of the Usher syndromes.Am J Med Genet.1994,50:32-38.
10.Scanlan MJ,Williamson B,Jungbluth A,et al.Isoforms of the human PDZ-73 protein exhibit differential tissue expression.Biochim Biophsy Acta.1999,1445:39-52.
11.Verpy E,Leibovici M,Zwaenepoel I,et al.A defect in harmonin,a PDZ domain-containing protein expressed in the inner ear sensory hair cells,underlies Usher syndrome type IC.Nature Genet.2000,26:51-55.
12.Adato A,Michel V,Kikkawa Y,et al.interactions in the network of Usher syndrome type 1 proteins.Hum Molec Genet.2005,14:347-356.
13.Ouyang XM,Hejtmancik JF,Jacobson SG.et al.USH1C:a rare cause of USH1 in a non-Acadian population and a founder effect of the Acadian allele.Clin Genet.2003,63:150-153.
14.Weil D,El-Amraoui A,Masmoudi S,et al.Usher syndrome type IG (USH1G)is caused by mutations in the gene encoding SANS,a protein that associates with the USH1C protein,harmonin.Hum Molec Genet.2003,12:463-471.
15.Kimberling WJ,Weston MD,Moller C,et al.Localization of Usher syndrome type Ⅱ to chromosal lq.Genomics.1990,7(2):245-249.
16.Eudy JD,Weston MD,Yao SF,et al.Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type Ⅱ.Science.1998,280:1753-1757.
17.Weston MD,Eudy JD,Fujita S,et al.Genomic structure and identification of novel mutation in Usherin,the gene responsible for Usher syndrome type IIa. Am J Hum Genet. 2000, 66:1199-1210
18. Liu XZ, Hope C, Liang CY, et al. A mutation (2314de1G) in the Usher syndrome type IIA gene: High prevalence and phenotypic variation. Am J Hum Genet . 1999. 64:1221-1225.
19. Rivolta C, Sweklo EA, Berson EL, et al. Missense mutation in the USH2A gene: Association with recessive retinitis pigmentosa without hearing loss. Am J Hum Genet. 2000. 66:1975-1978.
20. Mburu P, Mustapha M, Varela A, et al. Defects in whirl in, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nature Genet. 2003, 34: 421-428.
21. Kikkawa Y, Mburu P, Morse S, et al. Mutant analysis reveals whirlin as a dynamic organizer in the growing hair cell stereocilium. Hum Molec Genet. 2005, 14: 391-400.
[1]Wang DY,Chan WM,Tam POS et al.Gene mutations in retinitis pigmentosa and their clinical implications.Clinica Chimica Acta,2005,351(i-2):5
[2]Cohen M,Bitner-Glindzicz M,Luxon L.The changing face of Usher syndrome:clinical implications.Int J Audiol,2007,46(2):82
[3]Azari AA,Aleman TS,Cideciyan AV et al.Retinal disease expression in Bardet-Biedl syndrome-1(BBS1)is a spectrum from maculopathy to retina-wide degeneration,Invest Ophthalmol Vis Sci,2006,47(11):5004
[4]Rivolta C,Sharon D,DeAngelis MM et al.Retinitis pigmentosa and allied diseases:numerous diseases,genes,and inheritance patterns.Hum Mol Genet,2002,11(10):1219
[5]Kajiwara K,Berson EL,Dryla TP.Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci.Science,1994,264(5165):1604
[6]Katsanis N,Ansley SJ,Badano JL et al.Triallelic inheritance in Bardet-Biedl syndrome,a Mendelian recessive disorder.Science, 2001 293(5538):2256
[7]Dryjia TP, Li T. Molecular genetics of retinitis pigmentosa. Hum Mol Genet, 1995, 4:1739
[8]Nathans J, Hogness DS. Isolation and nucleotide sequence of the gene encoding human rhodopsin. Proc Natl Acad Sci USA, 1984, 81 (15):4851
[9]Cideciyan AV, Hood DC, Huang Y et al. Disease sequence from mutant rhodopsin allele to rod and cone photoreceptor degeneration in man. Proc Natl Acad Sci U S A. 1998, 95(12):7103
[10]SungCH, Davenport CM, Nathans J. Rhodopsin mutations responsible for autosomal dominant retinitis pigmentos-clustering of functional classes along the polypeptide chain. J Biol Chem, 1993, 268(35): 26645
[11]Andres A, Garriga P, Manyosa J, Altered functionality in rhodopsin point mutants associated with retinitis pigmentosa. Biochem Biophys Res Commun, 2003, 303(1):294
[12]van Soest S, Westerveld A, de Jong PT et al. Retinitis pigmentosa: defined from a molecular point of view. Surv Ophthalmol, 1999, 43(4): 321
[13]Berson EL, Rosner B,. Sandberg MA et al. Ocular findings in patients with autosomal dominant retinitis pigmentosa and a rhodopsin gene defect (Pro-23-His). Arch Ophthalmol, 1991, 109(1):92
[14]Oh KT, Longmuir R, Oh DM et al. Comparison of the clinical expression of retinitis pigmentosa associated with rhodopsin mutations at codon 347 and codon 23. Am. J. Ophthalmol, 2003, 136(2): 306
[15]Pierce EA, Quinn T, Meehan T et al. Mutations in a gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis pigmentosa. Nat Genet, 1999, 22(3):248
[16]Sullivan LS, Heckenlively JR, Bowne SJ et al. Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa. Nat Genet, 1999, 22(3):255
[17]Bowne SJ, Daiger SP, Hims MM et al. Mutations in the RP1 gene causing autosomal dominant retinitis pigmentosa. Hum Mol Genet, 1999, 8(11) :2121
[18]Ng HH, Bird A. DNA methylation and chromatin modification. Curr Opin Genet Dev, 1999, 9(2): 158
[19]Guillonneau X, Piriev NI, Danciger M et al. A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus. Hum Mol Genet. 1999, 8(8):1541
[20]Baum L, Chan WM, Yeung KY et al. RP1 in Chinese: Eight novel variants and evidence that truncation of the extreme C-terminal does not cause retinitis pigmentosa. Hum Mutat, 2001, 17(5):436
[21]Capeans C, Blanco MJ, Lareu MV et al. Linkage analysis in a large Spanish family with X-linked retinitis pigmentosa: phenotype-genotype correlation. Clin Genet, 1998, 54(1):26
[22]Meindl A, Dry K, Herrmann K et al. A gene (RPGR) with homology to the RCCl guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nat Genet, 1996, 13(1):35
[23]Bader I, Brandau O, Achatz H et al. X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15. Invest Ophthalmol Vis Sci, 2003, 44(4):1458
[24]Liu L, Jin L, Liu M et al. Identification of two novel mutations (E332X and c1536de1C) in the RPGR gene in two Chinese families with X-linked retinitis pigmentosa. Hum Mutat, 2000, 15(6):584
2.杨培增,陈家祺,葛坚,吴德正主编.眼科学基础与临床.北京:人民卫生出版社,2006,758-760.
3.Moller CG,Kimberling WJ,Davenport SL,et al.Usher syndrome:Anotoneurologic study.Laryngerscope.1989,99(1):73-9.
4.Boughman JA,Vernon M,shaver KA.Usher syndrome:definition and estimate of prevalence from two high-risk populations.J Chronic Dis.1983,36(8):595-603.
5.Kajiwara K,Berson EL,Dryja TP.Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci.Science.1994,264(5165):1604-8.
6.Pagon RA.Syndromic retinal dystrophy.Liviana Medicina.1993:pp.151-166.
7.李凤鸣主编.眼科全书.北京:人民卫生出版社,1999,624-701
8.Berson EL.Retinitis pigmentosa.Invest Ophthalmol Vis Sci.1993,34(5):1659-76.
9.Smith RJ,Berlin CI,Hejtmancik JF,et al.Clinical diagnosis of the Usher syndromes.Usher Syndrome Consortium.Am J Med Genet.1994,50(1):32-8.
10.《世界人类基因组与人权宣言》.联合国教科文组织第29届大会.巴梨黎.1997年11月11日.
11.《人类遗传资源管理暂行办法》.科技部、卫生部联合制定.北京.1998年6月.
12.RetNe http://www.sciencedirect.com/science?ob=RedirectURL&_method=ex ternObjhink&_locator=url&_cdi:4995&_plusSign=%2B&_targetURL=htt p%253A%252F%252Fwww.sph.uth.tmc.edu%252FRetNet%252F
13.van Soest S,Westerveld A,de Jong PT,et al.Retinitis pigmentosa:defined from a molecular point of view.Surv Ophthalmol.1999,43(4):321-34.
14.《赫尔辛基宣言》.第52届世界医学大会.苏格兰爱丁堡.2000年10月.
1.Travis GH.Mechanisms of cell death in the inherited retinal degenerations.Am J Hum Genet.1998,62(3):503-508.
2.Zack DJ.Birth and death in the retina:more related than we thought?Neuron.1999,23(3):549-55?.
3.Rimoin DL,Connor M,Pyeritz RE,et al.Hereditary retinal and choroidal degenerations.Edition(4th ed).New York.Churchill Living Stone.2002,3555-3593.
4.Pagon RA.Syndromic retinal dystrophy.Naples.Liviana Medicina.1993,151-166.
5. Nathans J, Hogness DS. Isolation and nucleotide sequence of the gene encoding human rhodopsin. Proc Natl Acad Sci USA. 1984, 81(15): 4851-5.
6. Andres A, GarrigaP, Manyosa J. Altered functionality in rhodopsin point mutants associated with retinitis pigmentosa. Biochem Biophys Res Commun. 2003, 303(1):294-301.
7. Sung CH, Davenport CM, Nathans J. Rhodopsin mutations responsible for autosomal dominant retinitis pigmentosa. Clustering of functional classes along the polypeptide chain. J Biol Chem. 1993, 268(35): 26645-49.
8. Roof DJ, Adamian M, Hayes A. Rhodopsin accumulation at abnormal sites in retinas of mice with a human P23H rhodopsin transgene . Invest Ophthalmol Vis Sci. 1994, 35(12):4049-62.
9. Roof DJ, Adamian M, Hayes A. Rhodopsin accumulation at abnormal sites in retinas of mice with a human P23H rhodopsin transgene . Invest Ophthalmol Vis Sci. 1994, 35(12):4049-62.
10. Bayés M, Martínez-Mir A, Valverde D, et al. Autosomal recessive retinitis pigmentosa in Spain: evaluation of four genes and two loci involved in the disease. Clin Genet. 1996, 50(5):380-7.
11. Sung CH, Davenport CM, Hennessey JC, et al. Rhodopsin mutations in autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A. 1991, 88(15): 6481-5.
12. Pannarale MR, Grammatico B, Iannaccone A, et al. Autosomal-dominant retinitis pigmentosa associated with an Arg-135-Trp point mutation of the rhodopsin gene. Clinical features and longitudinal observations. Ophthalmology. 1996, 103(9):1443-52.
13. Souied E, Soubrane G, Benlian P. et al. Retinitis punctata albescens associated with the Argl35Trp mutation in the rhodopsin gene. Am J Ophthalmol. 1996, 121(1):19-25.
14. Andreasson S, Ehinger B, Abrahamson M, et al. A six-generation family with autosomal dominant retinitis pigmentosa and a rhodopsin gene mutation (arginine-135-leucine). Ophthalmic Paediatr Genet. 1992, 13(3):145-53.
15. Min KC, Zvyaga TA, Cypess AM. Characterization of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. Mutations on the cytoplasmic surface affect transducin activation. J Biol Chem. 1993, 268(13):9400-4.
16. Travis GH, Christerson L, Danielson PE, et al. The human retinal degeneration slow (RDS) gene: chromosome assignment and structure of the mRNA. Genomics. 1991, 10(3): 733-9.
17. Travis GH, HeplerJE. A medley of retinal dystrophies. Nature Genet. 1993, 3(3): 191-2.
18. Nichols BE, Sheffield VC, Vandenburgh K, et al. Butterfly-shaped pigment dystrophy of the fovea caused by a point mutation in codon 167 of the RDS gene. Nature Genet. 1993, 3(3): 202-7.
19. Wroblewski JJ, Wells JA 3rd, Eckstein A, et al. Macular dystrophy associated with mutations at codon 172 in the human retinal degeneration slow gene. Ophthalmology. 1994, 101(1): 12-22.
20. Kohl S, Christ-Adler M, Apfelstedt-Sylla E, et al. RDS/peripherin gene mutations are frequent causes of central retinal dystrophies. J Med Genet. 1997, 34(8): 620-6.
21. Kajiwara K, Berson EL, Dryja TP. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROMl loci. Science. 1994, 264(5165):1604-8.
22. Nadeau JH. Modifier genes in mice and humans. Curr Opin Genet Dev. 2003, 13(3): 290-5.
23. Bascom RA, García-Heras J, Hsieh CL, et al. Localization of the photoreceptor gene ROMl to human chromosome 11 and mouse chromosome 19: sublocalization to human 11q13 between PGA and PYGM. Am J Hum Genet. 1992, 51(5):1028-35.
24. Bascom RA, Connell G, Garcia-Heras J, et al. Molecular and ultrastructural characterization of the products of the human retinopathy candidate genes R0M1 and RDS. Am J Hum Genet. 1990, 47 (suppl): A101.
25. Farjo Q, Jackson A, Pieke-Dahl S, et al. Human bZIP transcription factor gene NRL: structure, genomic sequence, and fine linkage mapping at 14qll. 2 and negative mutation analysis in patients with retinal degeneration. Genomics. 1997, 45(2):395-401.
26. Mitton KP, Swain PK, Khanna H, et al. Interaction of retinal bZIP transcription factor NRL with Flt3-interacting zinc-finger protein Fizl: possible role of Fizl as a transcriptional repressor. Hum Mol Genet. 2003, 12(4): 365-73.
27. Bessant DA, Holder GE, Fitzke FW, et al. Phenotype of retinitis pigmentosa associated with the ser50thr mutation in the NRL gene. Arch Ophthalmol. 2003, 121(6):793-802.
28. Furukawa T, Morrow EM, Cepko CL, et al. Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell. 1997, 91(4) :531-41.
29. Chen S, Wang QL, Xu S, et al. Functional analysis of cone-rod homeobox (CRX) mutations associated with retinal dystrophy. Hum Mol Genet. 2002, 11(8):873-84.
30. Rivolta C, Berson EL, Dryja TP. Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX. Hum Mutat. 2001, 18(6): 488-98.
1.Moller CG,Kimberling WJ,Davenport SLH,et al.Usher syndrome:Anotoneurologic study.Laryngerscope,1989,99:73-79.
2.Boughman JA,Vernon M,shaver KA,et al.Usher syndrome:definition and estimate of preverlence from two high-risk population.J Chronic Dis.1983,36:595-603.
3.Smith RJ,Berlin CI,Hejtmancik JF,et al.Clinical diagnostic of the Usher syndrome.Usher Syndrome Consortium.Am J Med Genet.1994,50:32-38.
4.Van Camp q Smith RJ.The Hereditary Hearing loss Homepage.http://webhost.ua.ac.be/hhh/.Lastupdated:February 16,2006.
5.Belal A.Usher's syndrome:a temporal bone report.J Iaryngol Otol,1975,89:175-181.
6.Shinkawa H,Nadol JB.Histopathology of the inner ear in Usher's syndrome as observed by light and electron microscopy.Ann Otol Rhinol Larygol,1986,95:313-317.
7.宋振英.Usher综合征.见:李凤鸣主编.眼科全书.北京:人民卫生出版社, 1996,3778-3779.
8.陈彭,赵明威,张承芬.视网膜色素变性.张承芬主编.眼底病学.北京:人民卫生出版社,1998,408-409.
9.Smith RJH,Berlin CI,Hejtmancik JF,et al.Clinical diagnosis of the Usher syndromes.Am J Med Genet.1994,50:32-38.
10.Scanlan MJ,Williamson B,Jungbluth A,et al.Isoforms of the human PDZ-73 protein exhibit differential tissue expression.Biochim Biophsy Acta.1999,1445:39-52.
11.Verpy E,Leibovici M,Zwaenepoel I,et al.A defect in harmonin,a PDZ domain-containing protein expressed in the inner ear sensory hair cells,underlies Usher syndrome type IC.Nature Genet.2000,26:51-55.
12.Adato A,Michel V,Kikkawa Y,et al.interactions in the network of Usher syndrome type 1 proteins.Hum Molec Genet.2005,14:347-356.
13.Ouyang XM,Hejtmancik JF,Jacobson SG.et al.USH1C:a rare cause of USH1 in a non-Acadian population and a founder effect of the Acadian allele.Clin Genet.2003,63:150-153.
14.Weil D,El-Amraoui A,Masmoudi S,et al.Usher syndrome type IG (USH1G)is caused by mutations in the gene encoding SANS,a protein that associates with the USH1C protein,harmonin.Hum Molec Genet.2003,12:463-471.
15.Kimberling WJ,Weston MD,Moller C,et al.Localization of Usher syndrome type Ⅱ to chromosal lq.Genomics.1990,7(2):245-249.
16.Eudy JD,Weston MD,Yao SF,et al.Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type Ⅱ.Science.1998,280:1753-1757.
17.Weston MD,Eudy JD,Fujita S,et al.Genomic structure and identification of novel mutation in Usherin,the gene responsible for Usher syndrome type IIa. Am J Hum Genet. 2000, 66:1199-1210
18. Liu XZ, Hope C, Liang CY, et al. A mutation (2314de1G) in the Usher syndrome type IIA gene: High prevalence and phenotypic variation. Am J Hum Genet . 1999. 64:1221-1225.
19. Rivolta C, Sweklo EA, Berson EL, et al. Missense mutation in the USH2A gene: Association with recessive retinitis pigmentosa without hearing loss. Am J Hum Genet. 2000. 66:1975-1978.
20. Mburu P, Mustapha M, Varela A, et al. Defects in whirl in, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nature Genet. 2003, 34: 421-428.
21. Kikkawa Y, Mburu P, Morse S, et al. Mutant analysis reveals whirlin as a dynamic organizer in the growing hair cell stereocilium. Hum Molec Genet. 2005, 14: 391-400.
[1]Wang DY,Chan WM,Tam POS et al.Gene mutations in retinitis pigmentosa and their clinical implications.Clinica Chimica Acta,2005,351(i-2):5
[2]Cohen M,Bitner-Glindzicz M,Luxon L.The changing face of Usher syndrome:clinical implications.Int J Audiol,2007,46(2):82
[3]Azari AA,Aleman TS,Cideciyan AV et al.Retinal disease expression in Bardet-Biedl syndrome-1(BBS1)is a spectrum from maculopathy to retina-wide degeneration,Invest Ophthalmol Vis Sci,2006,47(11):5004
[4]Rivolta C,Sharon D,DeAngelis MM et al.Retinitis pigmentosa and allied diseases:numerous diseases,genes,and inheritance patterns.Hum Mol Genet,2002,11(10):1219
[5]Kajiwara K,Berson EL,Dryla TP.Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci.Science,1994,264(5165):1604
[6]Katsanis N,Ansley SJ,Badano JL et al.Triallelic inheritance in Bardet-Biedl syndrome,a Mendelian recessive disorder.Science, 2001 293(5538):2256
[7]Dryjia TP, Li T. Molecular genetics of retinitis pigmentosa. Hum Mol Genet, 1995, 4:1739
[8]Nathans J, Hogness DS. Isolation and nucleotide sequence of the gene encoding human rhodopsin. Proc Natl Acad Sci USA, 1984, 81 (15):4851
[9]Cideciyan AV, Hood DC, Huang Y et al. Disease sequence from mutant rhodopsin allele to rod and cone photoreceptor degeneration in man. Proc Natl Acad Sci U S A. 1998, 95(12):7103
[10]SungCH, Davenport CM, Nathans J. Rhodopsin mutations responsible for autosomal dominant retinitis pigmentos-clustering of functional classes along the polypeptide chain. J Biol Chem, 1993, 268(35): 26645
[11]Andres A, Garriga P, Manyosa J, Altered functionality in rhodopsin point mutants associated with retinitis pigmentosa. Biochem Biophys Res Commun, 2003, 303(1):294
[12]van Soest S, Westerveld A, de Jong PT et al. Retinitis pigmentosa: defined from a molecular point of view. Surv Ophthalmol, 1999, 43(4): 321
[13]Berson EL, Rosner B,. Sandberg MA et al. Ocular findings in patients with autosomal dominant retinitis pigmentosa and a rhodopsin gene defect (Pro-23-His). Arch Ophthalmol, 1991, 109(1):92
[14]Oh KT, Longmuir R, Oh DM et al. Comparison of the clinical expression of retinitis pigmentosa associated with rhodopsin mutations at codon 347 and codon 23. Am. J. Ophthalmol, 2003, 136(2): 306
[15]Pierce EA, Quinn T, Meehan T et al. Mutations in a gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis pigmentosa. Nat Genet, 1999, 22(3):248
[16]Sullivan LS, Heckenlively JR, Bowne SJ et al. Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa. Nat Genet, 1999, 22(3):255
[17]Bowne SJ, Daiger SP, Hims MM et al. Mutations in the RP1 gene causing autosomal dominant retinitis pigmentosa. Hum Mol Genet, 1999, 8(11) :2121
[18]Ng HH, Bird A. DNA methylation and chromatin modification. Curr Opin Genet Dev, 1999, 9(2): 158
[19]Guillonneau X, Piriev NI, Danciger M et al. A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus. Hum Mol Genet. 1999, 8(8):1541
[20]Baum L, Chan WM, Yeung KY et al. RP1 in Chinese: Eight novel variants and evidence that truncation of the extreme C-terminal does not cause retinitis pigmentosa. Hum Mutat, 2001, 17(5):436
[21]Capeans C, Blanco MJ, Lareu MV et al. Linkage analysis in a large Spanish family with X-linked retinitis pigmentosa: phenotype-genotype correlation. Clin Genet, 1998, 54(1):26
[22]Meindl A, Dry K, Herrmann K et al. A gene (RPGR) with homology to the RCCl guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nat Genet, 1996, 13(1):35
[23]Bader I, Brandau O, Achatz H et al. X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15. Invest Ophthalmol Vis Sci, 2003, 44(4):1458
[24]Liu L, Jin L, Liu M et al. Identification of two novel mutations (E332X and c1536de1C) in the RPGR gene in two Chinese families with X-linked retinitis pigmentosa. Hum Mutat, 2000, 15(6):584