遗传性皮质性进展性白内障致病基因的研究
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摘要
目的:白内障是人类主要的致盲眼病,每10,000个新生儿就有1-6个先天性白内障,其中1/3是遗传性的。有三种不同的遗传方式:常染色体显性遗传,常染色体隐性遗传,性染色体连锁遗传,常染色体显性遗传是先天性白内障最常见的遗传方式。1963年,Renwick和Lawler在研究中发现一常染色体遗传性带样粉尘状白内障与杜非血型(Duffy blood group)位点发生共分离现象,1968杜非血型定位在1号染色体,先天性白内障也随之获得了第一个常染色体遗传位点。随着分子遗传学的发展,已不断发现几十个新的先天性白内障遗传位点,现在已明确18个白内障致病基因。但是基因型和表现型的关系尚不明确,遗传性和老年性白内障的关系还不清楚,对真正了解这一疾病的发病机制和防治还有很大的距离。我们通过对一个患皮质性进展性白内障的大家系,行致病基因定位和筛查的研究,希望发现可影响晶状体的相关基因,并探索其发病机制。
方法:
1.随访一个连续六代发病的白内障家系,签订知情同意书后,采集临床资料及血样标本,绘制系谱图,进行经典遗传学分析和细胞遗传学检查。
2.提取家系成员的基因组DNA,采用定位克隆的策略,首先在15个已知白内障基因所在的位点,每个位点选取3-4个微卫星标记排除已知基因。然后利用全基因组扫描试剂盒(ABI),共382个微卫星标记,每个间距约～10cM,初步定位。在定位区选取更多的微卫星标记,从Marshfield遗传数据库确定标记的顺序和位置。基因型和数据的收集利用ABI Prism GeneMapper(V3.0),利用LINKAGE(V5.10)中MLINK程序行两点连锁分析,计算Lod值。家系图和单体型的构建用Cyrillic(V2.1)软件。
3.根据物理图谱,选择定位区域内的候选致病基因,Genebank搜寻候选基因
Objective: Cataract remains the leading cause of human blindness worldwide. Congenital cataracts have an estimated frequency of 1 -6 per 10,000 live births, with one third of cases are familial. Congenital cataracts have been reported with all three types of Mendelian inheritance, autosomal dominant, autosomal recessive, and X-linked. Autosomal dominant congenital cataracts with high penetrance appear to be the most common in affected individuals. The autosomal dominant zonular pulverulent cataract (CAE1) locus was initially linked with the Duffy blood-group locus (Renwick and Lawler 1963), and, in 1968, the Duffy bloodgroup locus was assigned to chromosome 1. This mapped the CAE1 locus to human chromosome 1 (Donahue et al. 1968). To date, more than twenty autosomal dominant congenital cataract loci have been mapped to different chromosomal. Recent work in molecular genetics has identified 18 genes involved in the pathogenesis of isolated inherited cataract. However both the relation of genotype and phenotype and of hereditary and age related cataract are unclear. There is a long way to understand the mechenism and precaution of cataract. We studied a family suffering form cortical progressive cataract and. We carried out gene mapping and mutation screening and tried to identify the pathogenic gene and mechenism of cataract. Moreover cataractogenesis and its eventual therapeutic amelioration were investigated. Methods:1. We investigated a six-generation cataract family. After obtaining informed consent Clinical information and blood specimens were obtained from family
members. Then we performed Classic genetics and cytogenetics analysis.2. Genomic DNA was extracted from peripheral blood leucocytes. Firstly, we studied 11 loci for known candidate genes using three or four fluorescent microsatellite markers per locus and no evidence of linkage was detected. Subsequently a genomewide scan consisting of 382 microsatellite markers spaced at -10 cM intervals was performed using ABI PRISM Linkage Mapping sets. At last we performed fine mapping. The markers' order and position were obtained from the Marshfield Genetic Database. Genotyping and data collection were conducted by ABI Prism GeneMapper v 3.0 software. We carried out two-point linkage analysis using the MLINK program from the LINKAGE v.5.10 software package. Pedigree and haplotype construction were performed by Cyrillic v.2.1 software.3. Candidate genes were selected in the physical map. The sequences of the genes were got from genebank database. The primer was designed by Primer 3 software. We screened the mutation of candidate genes by bidirectional sequencing PCR products.4. We perform bioinformatics analysis of mutant protein, including physical character, function, structure and et al.Results:1. We studied a Chinese six-generation cataract family composed of 119 individuals with a dominant pattern of inheritance. Clinical information and blood specimens were obtained from 64 family members, including 14 patients. The phenotype in this family was characterized by opacities in cortex. The opacities can be located in anterior cortex, posterior or peripheral cortex but no opacity was observed in the fetal nuclear region. Moreover this cataract is of a progressive nature, and
cataractous changes were prominent in affected older individuals. Phenotypic variation in the size and density of opacities as well as the position was observed among the 14 affected members, even between the two lenses of an individual. From the pedigree, a autosome dominant pattern of inheritance was recognized. Chromosome2. After gene mapping and haplotype were performed, we identified a new autosomal dominant congenital cataract locus on chromosome 3q26.3-qter. The disease gene lay in the approximately 2.8 Mb physical intervals between D3S1571 and D3S3570. Linkage analysis gave a maximum two point LOD score 6.34 (9=0.00) for marker D3S1602.3. By sequencing CRYGS gene on two directions, we identified a 105G—>T (NMO17541) heterozygous mutation in exon 2 of CRYGS, resulting in a Gly-?Val substitution at codon 18 (NP060011) in 14 affected members. This mutation was not found in 50 unaffected members in this family, neither in 400 chromosomes of 200 unrelated control individuals, excluding the possibility of a rare polymorphism.4. we perform bioinformatics analysis of mutant protein, including function and structure. It has shown that the four-stranded greek key P-sheet peptide corresponding to crystallin fold forms an individual calcium-binding site, and the first calcium ligate at the residue next to the conserved aromatic amino acid of the sequence Y/E/WXXXXXXG, which is located at the end of the first p-strand. Gly is needed for forming a dihedral angle so it is irreplaceable. In this family just this Gly mutated, which may lead to structural alterations in the Ca2+-binding and -storing ability. Additionally, prediction of function sequence detect that "G[RK][RK]" is Amidation site. Gly mutatation may disturb this function, and
then effect the relation between crystallins. These might be novel mechanisms of cataract formation. Understanding non-structural properties of crystallins may be critical for understanding the malfunction in molecular cascades that lead to cataractogenesis and its eventual therapeutic amelioration. It may help to have an understanding of the disease etiology and contribute to better understanding of the function and properties of this gene. Perhaps this study of progressive phenotype and CRYGS mutation may provide insight into the cause of the more common sporadic form of age-related cataracts.Conclusion: Gamma-S crystalline gene (CRYGS) mutation causes hereditary cortical progressive cataract. This report is the first description of a mutation in CRYGS in humans and added another gene to growing list of genes involved in this heterogeneous monogenic disorder.
方法:
1.随访一个连续六代发病的白内障家系,签订知情同意书后,采集临床资料及血样标本,绘制系谱图,进行经典遗传学分析和细胞遗传学检查。
2.提取家系成员的基因组DNA,采用定位克隆的策略,首先在15个已知白内障基因所在的位点,每个位点选取3-4个微卫星标记排除已知基因。然后利用全基因组扫描试剂盒(ABI),共382个微卫星标记,每个间距约～10cM,初步定位。在定位区选取更多的微卫星标记,从Marshfield遗传数据库确定标记的顺序和位置。基因型和数据的收集利用ABI Prism GeneMapper(V3.0),利用LINKAGE(V5.10)中MLINK程序行两点连锁分析,计算Lod值。家系图和单体型的构建用Cyrillic(V2.1)软件。
3.根据物理图谱,选择定位区域内的候选致病基因,Genebank搜寻候选基因
Objective: Cataract remains the leading cause of human blindness worldwide. Congenital cataracts have an estimated frequency of 1 -6 per 10,000 live births, with one third of cases are familial. Congenital cataracts have been reported with all three types of Mendelian inheritance, autosomal dominant, autosomal recessive, and X-linked. Autosomal dominant congenital cataracts with high penetrance appear to be the most common in affected individuals. The autosomal dominant zonular pulverulent cataract (CAE1) locus was initially linked with the Duffy blood-group locus (Renwick and Lawler 1963), and, in 1968, the Duffy bloodgroup locus was assigned to chromosome 1. This mapped the CAE1 locus to human chromosome 1 (Donahue et al. 1968). To date, more than twenty autosomal dominant congenital cataract loci have been mapped to different chromosomal. Recent work in molecular genetics has identified 18 genes involved in the pathogenesis of isolated inherited cataract. However both the relation of genotype and phenotype and of hereditary and age related cataract are unclear. There is a long way to understand the mechenism and precaution of cataract. We studied a family suffering form cortical progressive cataract and. We carried out gene mapping and mutation screening and tried to identify the pathogenic gene and mechenism of cataract. Moreover cataractogenesis and its eventual therapeutic amelioration were investigated. Methods:1. We investigated a six-generation cataract family. After obtaining informed consent Clinical information and blood specimens were obtained from family
members. Then we performed Classic genetics and cytogenetics analysis.2. Genomic DNA was extracted from peripheral blood leucocytes. Firstly, we studied 11 loci for known candidate genes using three or four fluorescent microsatellite markers per locus and no evidence of linkage was detected. Subsequently a genomewide scan consisting of 382 microsatellite markers spaced at -10 cM intervals was performed using ABI PRISM Linkage Mapping sets. At last we performed fine mapping. The markers' order and position were obtained from the Marshfield Genetic Database. Genotyping and data collection were conducted by ABI Prism GeneMapper v 3.0 software. We carried out two-point linkage analysis using the MLINK program from the LINKAGE v.5.10 software package. Pedigree and haplotype construction were performed by Cyrillic v.2.1 software.3. Candidate genes were selected in the physical map. The sequences of the genes were got from genebank database. The primer was designed by Primer 3 software. We screened the mutation of candidate genes by bidirectional sequencing PCR products.4. We perform bioinformatics analysis of mutant protein, including physical character, function, structure and et al.Results:1. We studied a Chinese six-generation cataract family composed of 119 individuals with a dominant pattern of inheritance. Clinical information and blood specimens were obtained from 64 family members, including 14 patients. The phenotype in this family was characterized by opacities in cortex. The opacities can be located in anterior cortex, posterior or peripheral cortex but no opacity was observed in the fetal nuclear region. Moreover this cataract is of a progressive nature, and
cataractous changes were prominent in affected older individuals. Phenotypic variation in the size and density of opacities as well as the position was observed among the 14 affected members, even between the two lenses of an individual. From the pedigree, a autosome dominant pattern of inheritance was recognized. Chromosome2. After gene mapping and haplotype were performed, we identified a new autosomal dominant congenital cataract locus on chromosome 3q26.3-qter. The disease gene lay in the approximately 2.8 Mb physical intervals between D3S1571 and D3S3570. Linkage analysis gave a maximum two point LOD score 6.34 (9=0.00) for marker D3S1602.3. By sequencing CRYGS gene on two directions, we identified a 105G—>T (NMO17541) heterozygous mutation in exon 2 of CRYGS, resulting in a Gly-?Val substitution at codon 18 (NP060011) in 14 affected members. This mutation was not found in 50 unaffected members in this family, neither in 400 chromosomes of 200 unrelated control individuals, excluding the possibility of a rare polymorphism.4. we perform bioinformatics analysis of mutant protein, including function and structure. It has shown that the four-stranded greek key P-sheet peptide corresponding to crystallin fold forms an individual calcium-binding site, and the first calcium ligate at the residue next to the conserved aromatic amino acid of the sequence Y/E/WXXXXXXG, which is located at the end of the first p-strand. Gly is needed for forming a dihedral angle so it is irreplaceable. In this family just this Gly mutated, which may lead to structural alterations in the Ca2+-binding and -storing ability. Additionally, prediction of function sequence detect that "G[RK][RK]" is Amidation site. Gly mutatation may disturb this function, and
then effect the relation between crystallins. These might be novel mechanisms of cataract formation. Understanding non-structural properties of crystallins may be critical for understanding the malfunction in molecular cascades that lead to cataractogenesis and its eventual therapeutic amelioration. It may help to have an understanding of the disease etiology and contribute to better understanding of the function and properties of this gene. Perhaps this study of progressive phenotype and CRYGS mutation may provide insight into the cause of the more common sporadic form of age-related cataracts.Conclusion: Gamma-S crystalline gene (CRYGS) mutation causes hereditary cortical progressive cataract. This report is the first description of a mutation in CRYGS in humans and added another gene to growing list of genes involved in this heterogeneous monogenic disorder.
引文
1. Lambert SL, Drack AV Infantile cataracts. Surv Ophthalmol 1996;40: 427-58
2. Francois J. Genetics of cataract. Ophthalmologica 1982;184: 61-71
3. Ionides A et al. Clinical and genetic heterogeneity in autosomal dominant congenital cataract. Br J Ophthalmol 1999;83: 802-808
4. Ciulla TA, North K, McCabe O, et al. Bilateral infantile cataractogenesis in a patient with defiency of complex Ⅰ, a mitochondrial electron transport chain enzyme. J Pediatr Ophthalmol Strabismus 1995;32: 378-382
5. Pitkanen S, Merante F, McLeod DR, et al. Familial cardiomyopathy with cataracts and lactic acidosis: a defect in complex Ⅰ(NADH-dehydrogenase) of the Mitochondria respiratory chain. Ped Res 1996;39: 513-521
6. Cursiefen C, Kuchle M, Scheurlen W, et al. Bilateral zonular cataract associated with the mitochondrial cytopathy of Pearson syndrome. Am J Ophthalmol 1998;125: 260-261
7. Vanita Berry, Peter Francis, M Ashwin Reddy, et al.Alpha-B crystalline gene(CRYAB) mutation causes dominant congenital posterior polar cataract in humans.Am J Hum Genet 2001, 69: 1141-1145.
8. Litt M, Carrero-valenzuela R, Lamorticella D, et al.Autosomal dominant congenital cataract is associated with a chain termination mutation in the human beta-crystallin gene CRYBB2.Hum Mol Genet 1997;6: 665-668.
9. Kannabiran C, Rogan P, Olmos Let al.Autosomal dominant zonular cataract with sutural opacities is associated with splice mutation in the beta A3/Al-crystallin gene.Mol Vis 1998;4: 21.
10. Heon E, Priston M, Schorederet D, et al.The gamma-crystallins and human cataracts: a puzzle made clearer.Am J Hum Genet 1999;65: 1261-7.
11. Stephan D,Gillanders E,Vanderveen D,et al.Progressive juvenile-onset punctate cataract characterized by mutation of gamma-D-crystallin gene.Proc Natl Acad Sci USA 1999;96:1008-12
12. Mackay DS, Boskovska OB, Knopf HL, et al. A nonsense mutation in CRYBB1 associated with autosomal dominant cataract linked to human chromosome 22q.Am J Hum Genet. 2002 Nov;71(5):1216-21.
13. Riazuddin SA, Yasmeen A, Yao W, et al. Mutations in betaB3-crystallin associated with autosomal recessive cataract in two Pakistani families. Invest Ophthalmol Vis Sci. 2005 Jun;46(6):2100-6.
14. Ackay DJonides A,Kibar Z,et al.Connexin 46 mutations in zutosomal diminant congenital cataract.Am J Hum Genet 1999;64:1357-64.
15. Hiels A,Mackay D,et al .A missense mutation in the human connexin 50 gene(GJA8) underlies autosomal dominant "zonular pulverulent" cataract,on chromosome 1q.Am J Hum Genet 1998;62:526-32.
16. Peter Francis,Vanita Berruy,Ahomi Bhattacharya,et al.Congenital progressive polymorphic cataract caused by a mutation in the major intrinsic protein of the lens,MIP(AQPO).Br J Ophthalmol 2000;84:1376-1379.
17. Pras E, Levy-Nissenbaum E, Bakhan T,et al. A missense mutation in the LIM2 gene is associated with autosomal recessive presenile cataract in an inbred Iraqi Jewish family.Am J Hum Genet. 2002 May;70(5): 1363-7.
18. Petra M.Jakobs,John F.Hess,Paul GFitrzgerald et al.Autosomal dominant congenital cataract associated with a deletion mutation in the human beaded filament protein gene BFSP2.Am J Hum Genet 2000;66:1432-1436.
19. Semina E,Ferrell R,Mintz-Hittner H,et al.A novel homeobox gene PITX3 is mutation in families with autosomal dominant cataracts and ASMD.Nat Genet
1998;19: 167-170.
20. Glaser T, Jepeal L et al. PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet. 1994 Aug;7(4): 463-71.
21. Lei Bu, Yiping Jin, Yuefeng Shi, Renyuan Chu, et al.Mutant DNA binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract.Nature genetics 2002;31(7)
22. Jamieson RV, Perveen R, Kerr B, et al. Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma.Hum Mol Genet. 2002 Jan 1;11(1): 33-42.
23. Pars E, Raz J, Yahalom V, et al. A nonsense mutation in the glucosaminyl "(N-acetyl) transferase 2 gene(GCNT2): association with autosomal recessive congenital cataracts.Invest Ophthalmol Vis Sci. 2004 Jun;45(6): 1940-5.
24. Graw J, Cataract mutations as a tool for dewelopment geneticists.Ophthalmic Res 1996;28(supplel): 8-18
25. Nettleship E. A peculiar form of congenital cataract. Trans Ophthal Soc UK. 1906;26: 191-206
26.李璞《医学遗传学》北京:北京医科大学、中国协和医科大学联合出版,1999
27.贺林《解码生命》 北京:科学出版社,2000
28.江三多《医学遗传数理统计方法》 北京科学出版社,1998:66-70
29.沈福民《遗传医学》 上海医科大学出版社,1994:19-22
30. Francis Po J, Berru V, Bhattacharya s s et al.The genetics of childhood cataract. J Med Genet 2000;37: 481-488.
31. Mark H, Laura A, Murie.L et al.Autosimal dominant congenital cataract interrocular phenotypic variability.Ophthalmology 1994,101(5):866-871
32. Onneally PM, Wallace MR, Gusella JF, et al. Huntington disease: estimation of heterozygote status using linked genetic markers. Genet Epidemiol 1984;1(1): 81-88.
33. Donis-Keller H, Green P, Helms C, et al. A genetic linkage map of the human genome. Cell 1987;51(2): 319-337.
34. Dib C, Faure S, Fizames C,et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 1996;380(6570): 152-154.
35. Lander ES.The new genomics: global views of biology. Science. 1996 Oct25;274(5287):536-9
36. Kruglyak L,Daly MJ. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 1996;58:1347-1363
37. Uberbacher EC,et al. Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. Proc Natl Acad Sci.USA, 1991;88:11261
38. Ren wick JH, Lawler SD. Probable linkage between a congenital cataract locus and the Duffy blood group locus. Ann Hum Genet 1963;27:67-69
39. Donahue RP, Bias WB, Renwick JH et al. Probalbe assignment of the Duffy blood group locus to chromosome 1 in man. Proc Nat Acad Sci, 1968;61(3):949-955
40. Horwit J.Alpha-crystallin.Experimental Eye Research.2003;76:145-153
41. Daniel L,Boyle, Larry Takemoto,et al.A possible role for α-crystallins in lens epithelial cell differentiation. Molecular vision 2000;6:63-71.
42. Siva LV kumar,T Ramakrishna,CH Mohan Rao,et al.Structural and functional consequences of the mutation of a conserved Argeinine residue in αA and αB
crustallins. Journal of Biological chemistry 1999;274(34):2413 7-24141.
43. Gill D,Klose R,Munier F,et al.Genetic heterogeneity of the coppock-like cataracta mutation in CRYBB2 on chromosome 22q11.2.Invest Ophthalmol Vis Sci2000;41:159-165.
44. Errini W, Schorderet DF et al. CRYBA3/A1 gene mutation associated with suture-sparing autosomal dominant congenital nuclear cataract: a novel phenotype. Invest Ophthalmol Vis Sci. 2004 May;45(5):1436-41.
45. Bateman JB, Geyer DD et al. A new betaA1-crystallin splice junction mutation in autosomal dominant cataract. Invest Ophthalmol Vis Sci. 2000 Oct;41(11):3278-85.
46. van Rens GL, de jong WW and Bloemendal HA. Superfamily in the mammalian eye lens: the beta/gamma-crystallins Mol Biol Rep 1992;16:1-10.
47. Lubsen NH, Aarts HJ and Schoenmakers JG. The evolution of lenticular proteins: the beta- and gamma-crystallin super gene family. Prog Biophys Mol Biol 1988;51:47-76.
48.van Rens GL, Raats JM and Driessen HR Structure of the bovine eye lens gamma s-crystallin gene (formerly beta s). Gene 1989;78:225-33.
49. Jaworski C, Wistow G. LP2, a differentiation-associated lipid-binding protein expressed in bovine lens. Biochem J 1996;320:49-54.
50. Sinha D, Esumi N, Jaworski C, et al. Cloning and mapping the mouse Crygs gene and non-lens expression of [gamma]S-crystallin.. Mol Vis 1998;4:8
51. Bagby S, Harvey TS and Kay LE. Unusual helix-containing Greek keys in development-specific Ca~(2+)-binding protein S. ~1H, ~(15)N, and ~(13)C assignments and secondary structure determined with the use of multidimensional double and triple resonance heteronuclear NMR spectroscopy. Biochemistry 1994;33:2409-21.
52. Giuseppe DA. The evolution of monomeric and oligomeric βγ-type crystallins. Eur J Biochem 2002;269:3122-30.
53. Sinha D, Wyatt MK and Sarra R. temperature-sensitive mutation of Crygs in the murine Opj cataract. J Biol Chem 2001;276:9308-9315.
54. Bu L,Yan SS and Jin ML. the yS-crystallin gene is mutated in autosomal recessive cataract in mouse. Genomics 2002;80(1):38-44.
2. Francois J. Genetics of cataract. Ophthalmologica 1982;184: 61-71
3. Ionides A et al. Clinical and genetic heterogeneity in autosomal dominant congenital cataract. Br J Ophthalmol 1999;83: 802-808
4. Ciulla TA, North K, McCabe O, et al. Bilateral infantile cataractogenesis in a patient with defiency of complex Ⅰ, a mitochondrial electron transport chain enzyme. J Pediatr Ophthalmol Strabismus 1995;32: 378-382
5. Pitkanen S, Merante F, McLeod DR, et al. Familial cardiomyopathy with cataracts and lactic acidosis: a defect in complex Ⅰ(NADH-dehydrogenase) of the Mitochondria respiratory chain. Ped Res 1996;39: 513-521
6. Cursiefen C, Kuchle M, Scheurlen W, et al. Bilateral zonular cataract associated with the mitochondrial cytopathy of Pearson syndrome. Am J Ophthalmol 1998;125: 260-261
7. Vanita Berry, Peter Francis, M Ashwin Reddy, et al.Alpha-B crystalline gene(CRYAB) mutation causes dominant congenital posterior polar cataract in humans.Am J Hum Genet 2001, 69: 1141-1145.
8. Litt M, Carrero-valenzuela R, Lamorticella D, et al.Autosomal dominant congenital cataract is associated with a chain termination mutation in the human beta-crystallin gene CRYBB2.Hum Mol Genet 1997;6: 665-668.
9. Kannabiran C, Rogan P, Olmos Let al.Autosomal dominant zonular cataract with sutural opacities is associated with splice mutation in the beta A3/Al-crystallin gene.Mol Vis 1998;4: 21.
10. Heon E, Priston M, Schorederet D, et al.The gamma-crystallins and human cataracts: a puzzle made clearer.Am J Hum Genet 1999;65: 1261-7.
11. Stephan D,Gillanders E,Vanderveen D,et al.Progressive juvenile-onset punctate cataract characterized by mutation of gamma-D-crystallin gene.Proc Natl Acad Sci USA 1999;96:1008-12
12. Mackay DS, Boskovska OB, Knopf HL, et al. A nonsense mutation in CRYBB1 associated with autosomal dominant cataract linked to human chromosome 22q.Am J Hum Genet. 2002 Nov;71(5):1216-21.
13. Riazuddin SA, Yasmeen A, Yao W, et al. Mutations in betaB3-crystallin associated with autosomal recessive cataract in two Pakistani families. Invest Ophthalmol Vis Sci. 2005 Jun;46(6):2100-6.
14. Ackay DJonides A,Kibar Z,et al.Connexin 46 mutations in zutosomal diminant congenital cataract.Am J Hum Genet 1999;64:1357-64.
15. Hiels A,Mackay D,et al .A missense mutation in the human connexin 50 gene(GJA8) underlies autosomal dominant "zonular pulverulent" cataract,on chromosome 1q.Am J Hum Genet 1998;62:526-32.
16. Peter Francis,Vanita Berruy,Ahomi Bhattacharya,et al.Congenital progressive polymorphic cataract caused by a mutation in the major intrinsic protein of the lens,MIP(AQPO).Br J Ophthalmol 2000;84:1376-1379.
17. Pras E, Levy-Nissenbaum E, Bakhan T,et al. A missense mutation in the LIM2 gene is associated with autosomal recessive presenile cataract in an inbred Iraqi Jewish family.Am J Hum Genet. 2002 May;70(5): 1363-7.
18. Petra M.Jakobs,John F.Hess,Paul GFitrzgerald et al.Autosomal dominant congenital cataract associated with a deletion mutation in the human beaded filament protein gene BFSP2.Am J Hum Genet 2000;66:1432-1436.
19. Semina E,Ferrell R,Mintz-Hittner H,et al.A novel homeobox gene PITX3 is mutation in families with autosomal dominant cataracts and ASMD.Nat Genet
1998;19: 167-170.
20. Glaser T, Jepeal L et al. PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet. 1994 Aug;7(4): 463-71.
21. Lei Bu, Yiping Jin, Yuefeng Shi, Renyuan Chu, et al.Mutant DNA binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract.Nature genetics 2002;31(7)
22. Jamieson RV, Perveen R, Kerr B, et al. Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma.Hum Mol Genet. 2002 Jan 1;11(1): 33-42.
23. Pars E, Raz J, Yahalom V, et al. A nonsense mutation in the glucosaminyl "(N-acetyl) transferase 2 gene(GCNT2): association with autosomal recessive congenital cataracts.Invest Ophthalmol Vis Sci. 2004 Jun;45(6): 1940-5.
24. Graw J, Cataract mutations as a tool for dewelopment geneticists.Ophthalmic Res 1996;28(supplel): 8-18
25. Nettleship E. A peculiar form of congenital cataract. Trans Ophthal Soc UK. 1906;26: 191-206
26.李璞《医学遗传学》北京:北京医科大学、中国协和医科大学联合出版,1999
27.贺林《解码生命》 北京:科学出版社,2000
28.江三多《医学遗传数理统计方法》 北京科学出版社,1998:66-70
29.沈福民《遗传医学》 上海医科大学出版社,1994:19-22
30. Francis Po J, Berru V, Bhattacharya s s et al.The genetics of childhood cataract. J Med Genet 2000;37: 481-488.
31. Mark H, Laura A, Murie.L et al.Autosimal dominant congenital cataract interrocular phenotypic variability.Ophthalmology 1994,101(5):866-871
32. Onneally PM, Wallace MR, Gusella JF, et al. Huntington disease: estimation of heterozygote status using linked genetic markers. Genet Epidemiol 1984;1(1): 81-88.
33. Donis-Keller H, Green P, Helms C, et al. A genetic linkage map of the human genome. Cell 1987;51(2): 319-337.
34. Dib C, Faure S, Fizames C,et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 1996;380(6570): 152-154.
35. Lander ES.The new genomics: global views of biology. Science. 1996 Oct25;274(5287):536-9
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