杨正林-眼睛单基因疾病诊断

1、眼睛单基因疾病的早期诊断杨正林电子科技大学医学院四川省医学科院/四川省人民医院中国科学院四川转化医学研究医院 1. 遗传物质的存在 2. 遗传与分离规律 3. 显性遗传和隐性遗传规律/wiki/X-连锁遗传规律/wiki/核酸（nuclein（now nucleic acids）的发现/wiki/核苷酸碱基（A T G C U)的发现/wiki/遗传物质DNA与基因和染色体的联系（1944）DNA结构DNA测序Human

2、 Genome ProjectCompleted in 2003, the Human Genome Project (HGP) was a 13-year project coordinated by the U.S. Department of Energy and the National Institutes of Health. During the early years of the HGP, the Wellcome Trust (U.K.) became a major partner; additional contributions came from Japan, Fr

3、ance, Germany, China, and others.identify all the approximately 20,000-25,000 genes in human DNA,determine the sequences of the 3 billion chemical base pairs that make up human DNA,store this information in databases,improve tools for data analysis,transfer related technologies to the private sector

4、, andaddress the ethical, legal, and social issues (ELSI) that may arise from the project.Though the HGP is finished, analyses of the data will continue for many years.测序花费直线下降单基因疾病（polygenic diseases)多基因疾病 (polygenic diseases)- 3 -光信号化学信号基因突变不可逆的视力下降甚至失明视觉形成/education/material

5、s/HyperVis/vision/eyebrain.ht mPtosis(眼睑下垂）Most cases are in syndromesA number sign (#) is used with this entry because the blepharophimosis-ptosis- intellectual disability syndrome (BPIDS) is caused by heterozygous mutation in the UBE3B gene (608047) on chromosome 12q23./wiki/

6、Ptosis_(eyelid) omimStrabismus(斜视）Overall, esotropia is more common than exotropia.先天性眼外肌纤维化congenital fibrosis of extraocularmuscles-1 (CFEOM1) is caused by heterozygous mutation in the KIF21A gene (608283) on chromosome 12q12CFEOM2 (602078), an autosomal recessive disorder caused by mutation in th

7、e ARIX gene (602753) on chromosome 11q13, is characterized by bilateral ptosis with eyes fixed in an exotropic position./wiki and OMIMNystagmus(眼球震颤)most cases are in syndromesA number sign (#) is used with this entry because of evidence that childhood-onsetneurodegeneration wi

8、th optic atrophy (NDGOA) is caused by homozygous mutation in the UCHL1 gene (191342) on chromosome 4p14. One such family has been reported.A form of autosomal recessive nonsyndromic deafness designated DFNB84A (613391), which also maps to chromosome 12q21, is caused by mutation in the PTPRQ gene (60

9、3317).A number sign (#) is used with this entry because of evidence that X-linked congenital nystagmus-1 (NYS1) and infantile periodic alternating nystagmus (XIPAN) are caused by mutation in the FERM domain-containing-7 gene (FRMD7; 300628) on chromosome Xq26.OMIMCorneal

10、DystrophyFifteen genes out of nineteen lociKlintworth et al. Orphanet Journal of Rare Disease 2009格子状角膜营养变性 (lattice corneal dystrophy )-TGFBIABCD(exon4:c.C370T:p.R124C)共聚焦显微镜显示角膜呈糜烂状先天性无虹膜伴晶体脱位先天性无虹膜合并白内障(congenital aniridia and cataract)-PAX6 对该家系进行测序扫描，发现PAX6新的突变；I12II12345III12453IV12白内障最常见眼睛遗传病

11、至少有35个基因 /cataracts_pict ures_slideshow/article.htm先天性白内障家系 (autosomal dominant congenital cataract)-GJA8 对该家系进行测序扫描，发现GJA8新的突变；先天性白内障患者家系图林婴等医学遗传学杂志2008年 第1期 59-62页青光眼分类 先天性青光眼 原发性青光眼 开角性青光眼（POAG）（西方国家主要） 闭角性青光眼（PACG）（我国青光眼的一半以上） 继发性青光眼 混合性青光眼 正常眼底图患者视正常视青光眼青光眼以周围视力丢失为主要临床特

12、征青光眼基因 GLC1A (1q23, MYOC) （POAG), (显性) GLC3A (2p21, CYP1B1) （先天性）, RIEG1 (4q25, PITX2)(（ 先 天 性 ）), GLC1G (5q22, WDR36)(POAG), (显性) IRID1 (6p25, FOXC1) （先天性）,Nail patella syndrome (NPS) (9q34, LMX1B), (显性) GLC1E (10p15-p14, OPTN) (隐性)AN2 (11p13, PAX6) (显性)LTBP2 (14q24.3) （先天性） LTBP2unaffetedLTBP2:NM_

13、000428:exon14:c.G2421A:p.W807XaffetedCYP1B1unaffetedaffetedCYP1B1:NM_000104:exon3:c.C1198T:p.P400S,青光眼突变家系/retnet//retnet//retnet//retnet/Retinitis Pigmentosa特点：双眼视网膜周围视野减弱或消失，暗视野功能减弱或消失，发病率1/3000。骨样色素沉着为其特征。 视网膜

14、色素变性（RP）-PRPF31 对该家系进行测序扫描，发现PRPF31新的突变；Lu F. et al .PLoS One. 2013 Nov11;8(11):e78274.Juvenile Macular Dystrophy单纯性或原发性青少年黄斑变性疾病名称 位点 基因 常染色体隐性 STGD11p21-p13ABCA4常染色体显性 STGD36q14ELOVL4AVMD, PMD6q14RDSSTGD44q21PROM1BEST111q13VMD2SFD22q13-qterTIMP3DHRD2p16EFEMP1MCDR1/PBCRA6q11-q16.2unknownMCDR35q13.1

15、-p15.3unknownMCDR414qunknownMCDR519q13unknownDCMD7p15unknownMacular degeneration(MCDR3) 5p13.1-p15.33(MCDR4)14q(MCDR5) 19q13Michaelides, et al. Invest Ophthalmol Vis Sci, 2003. 44(5): p. 2178-83. Francis et al. Br J Ophthalmol, 2003. 87(7): p. 893-8. Yang et al. J Med Genet, 2006. 43(12): p. e57.Ped

16、igrees of autosomal dominant macular dystrophy &segregation of a PROM1 mutationRetinal degeneration as a consequence ofmutant R373C PROM1An India Family with RP caused by mutant PROM1Maw et al. Human Molecular Genetics, 2000, 9(1) 27-34A consanguineous Pakistani familywith a PROM1 mutationFundus pic

17、tures: RP and MDZhang et al. Human Genet (2007) 122:293-299PROM1 1726CT mutation in the Pakistani familyZhang et al. Human Genet (2007) 122:293-299PROM1 was expressed in both cone and rodphotoreceptors at the base of OSYang et al. 2008 Journal of Clinical InvestigationTransgenic mice expressing R373

18、C human mutationshow progressive deterioration of ERGSElectron microscopy of PROM1 transgenicmouse rod photoreceptorsYang et al. 2008 Journal of Clinical InvestigationMislocalization of mutant PROM1 in photoreceptorsHuman PROM1Mouse Prom1MergeCo-immunoprecipitation of PROM1/PCDH21, andproteolytic cl

19、eavage of PCDH21Co-immunoprecipitation of PROM1 and b-actinPROM1 promotes growth ofmembrane processesModel of disk morphogenesisKleinman & Ambati, JCI, 2008视网青少年黄斑变性家系（ Stargardt Disease）-ABCA4 对该家系进行外显子测序分析，发现ABCA4新的突变；Zhou Y. et al PLoS One. 2014 Mar 14;9(3):e91962. doi: 10.1371/journal.pone.00919

20、62.Familial exudative retinopathy (FEVR)1.The growth and rupture of abnormal blood vessels (vascularization) in the outer edges of the retina called the peripheral region.2. Blood vessel growth can occur at a rapid and continuous pace.3. Bleeding of these blood vessels can lead to dragging of the re

21、tina called retinal traction, and may result in scarring and/or retinal detachment due to the pulling of the retina.性渗出性玻璃体视网膜病变（FEVR）-TSPAN12 对3个FEVR家系进行测序扫描，发现c.566GA (p.C189Y), c.177delC (p.Y59fsX67)和c.C254T (p.T85M). 这三个FZD4新的致病突变； 功能研究发现这三个突变导致TSPAN12没有活性，影响Norrin信号通路的激活。Xu Y, Huang L, Li J, Zh

22、ang Q, Fei P, Zhu X, Tai Z, Ma S, Gong B, Li Y, Zang W, Zhu X, Zhao P, Yang Z. Novel mutations in the TSPAN12 gene in Chinese patients with familial exudative vitreoretinopathy. Mol Vis. 2014 Sep 20;20:1296-306性渗出性玻璃体视网膜病变（FEVR）-LRP5 对2个FEVR家系进行测序扫描，发现p.A422T 和 p.L540P 这两个FZD4新的致病突变； 功能研究发现这二个突变导致LR

23、P5没有活性，影响Norrin信号通路的激活。家系1家系2Fei P, Zhang Q, Huang L, Xu Y, Zhu X, Tai Z, Gong B, Ma S, Yao Q, Li J, Zhao P, Yang Z. Identification of two novel LRP5 mutations in families with familial exudative vitreoretinopathy. Mol Vis. 2014 Mar 29; 20: 395-409.巴尔得-别德尔综合征（ BardetBiedl syndrome ）-BBS7 对该家系进行关联分析，发现ABCA4新的突变；眼球缺损先天性小眼球 (27genes)只有眼球缺损PAX6 (MIM 607108), SHH (MIM600725), GDF3 (MIM 606522) RBP (MIM 180250)27 coloboma-associated genes, mutations in CHX10 (MIM 142993), MAF (MIM 177075), SOX2 (MIM