A new locus for autosomal recessive nuclear cataract mapped to chromosome 19q13 in a Pakistani family

PURPOSE: To identify the disease locus of autosomal recessive congenital nuclear cataracts in a consanguineous Pakistani family. METHODS: A large Pakistani family with multiple individuals affected by autosomal recessive congenital cataracts was ascertained. Patients were examined, blood samples were collected, and DNA was isolated. A genome-wide scan was performed using 382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members. Two-point lod scores were calculated, and haplotypes were formed by inspection. RESULTS: In the genome-wide scan, a maximum lod score of 2.89 was obtained for marker D19S414 on 19q13. Fine mapping using D19S931, D19S433, D19S928, D19S225, D19S416, D19S213, D19S425, and D19S220 markers from the Généthon database showed that markers in a 14.3-cM (12.66-Mb) interval flanked by D19S928 and D19S420 cosegregated with the cataract locus. Lack of homozygosity further suggests that the cataract locus may lie in a 7-cM (4.3-Mb) interval flanked by D19S928 proximally and D19S425 distally. On fine mapping, a maximum lod score of 3.09 was obtained with D19S416 at theta = 0. CONCLUSIONS: Linkage analysis identified a new locus for autosomal recessive congenital nuclear cataracts on chromosome 19q13 in a consanguineous Pakistani family.     

A new locus for autosomal dominant cataract on chromosome 12q13

PURPOSE: To map the gene for autosomal dominant cataracts (ADC) in an American white family of European descent. METHODS: Ophthalmic examinations and linkage analyses using a variety of polymorphisms were performed; two-point lod scores calculated. RESULTS: Affected individuals (14 studied) exhibited variable expressivity of embryonal nuclear opacities based on morphology, location within the lens, and density. This ADC locus to 12q13 was mapped on the basis of statistically significantly positive lod scores and no recombinations (theta(m) = theta(f) = 0) with markers D12S368, D12S270, D12S96, D12S359, D12S1586, D12S312, D12S1632, D12S90, and D12S83; assuming full penetrance, a maximum lod score of 4.73 was calculated between the disease locus and D12S90. CONCLUSIONS: The disease in this family represents the first ADC locus on chromosome 12; major intrinsic protein of lens fiber (MIP) is a candidate gene.     

A novel mutation of LIM2 causes autosomal dominant membranous cataract in a Chinese family

AIM: To determine the prevalence and associations of non-retinopathy ocular conditions among older Australian adults with diabetes. METHODS: Multistage random-cluster sampling was used to select 3098 non-indigenous Australians aged 50y or older (46.4% male) and 1738 indigenous Australians aged 40y or older (41.1% male) from all levels of geographic remoteness in Australia. Participants underwent a standardised questionnaire to ascertain diabetes history, and a clinical examination to identify eye disease. We determined the prevalence of uncorrected refractive error, visually significant cataract, cataract surgery, age-related macular degeneration, glaucoma, ocular hypertension, retinal vein occlusion and epiretinal membrane among those with and without self-reported diabetes. RESULTS: Participants with self-reported diabetes had a higher prevalence of cataract surgery than those without diabetes (28.8% vs 16.9%, OR 1.78, 95%CI: 1.35-2.34 among non-indigenous Australians, and 11.3% vs 5.2%, OR 1.62, 95%CI: 1.22-2.14 among indigenous Australians). Diabetic retinopathy (DR) increased the odds of cataract surgery among self-reported diabetic indigenous and non-indigenous Australians (OR 1.89, P=0.004 and OR 2.33, P<0.001 respectively). Having diabetes for ≥20y and having vision-threatening DR increased the odds of cataract surgery among indigenous Australians with diabetes (OR 3.73, P=0.001 and 7.58, P<0.001, respectively). CONCLUSION: Most non-retinopathy ocular conditions are not associated with self-reported diabetes. However, to account for Australia’s worsening diabetes epidemic, interventions to reduce the impact of diabetes-related blindness should include increased cataract surgery services.     

常染色体显性遗传白内障一家系基因排除定位研究

目的 对一个4代常染色体显性遗传性先天性白内障（ADCC）家系进行致病基因的定位。方法 对家系所有成员进行眼部检查。选取位于1、2、3、10、11、12、13、16、17、21及22号染色体上已知与ADCC相关的14个致病基因附近的微卫星标记物，并进行多重PCR扩增，经ABI3130型遗传分析仪，Genscan 2．1收集数据，Genotyper 2．1进行基因分型，Linkage软件计算两点LOD值。结果 未发现所选微卫星位点与该家系疾病表型共分离，LOD值均为负值。致病基因与已知的ADCC14个候选基因不存在连锁关系。结论 在此家系中存在新的致病基因有待于进一步的研究。     

A new locus for autosomal dominant congenital cataracts maps to chromosome 3

PURPOSE: To map a gene for cataracts in a family with congenital nuclear and sutural cataracts and to examine candidate genes in the linked region. METHODS: A large family with autosomal dominant congenital nuclear and sutural cataracts was identified and characterized. A genome-wide screen was conducted with a set of markers spaced at 10- to 15-cM intervals, and linkage was assessed using standard LOD score analysis. RESULT: Fifteen (15) affected individuals were identified. This form of congenital cataracts maps to a 12-cM region on chromosome 3q21.2-q22.3 between markers D3S3674 and D3S3612, with a maximum multipoint LOD score of 6.94 at D3S1273. The crystallin gene, CRYGS, was excluded as a candidate gene for this locus. CONCLUSIONS: There are now more than 12 different genetic loci that cause congenital cataracts. The most recent locus to be identified is on chromosome 3q21.2-q22.3, in a family with congenital nuclear and sutural cataracts.     

A new locus for autosomal recessive RP (RP29) mapping to chromosome 4q32-q34 in a Pakistani family

PURPOSE: To map the disease locus in a six-generation, consanguineous Pakistani family with autosomal recessive retinitis pigmentosa (arRP). All affected individuals had pigmentary retinopathy associated with symptoms of night blindness and the loss of peripheral visual fields by the age of 20 years, loss of central vision between the ages of 25 and 30 years, and complete blindness between the ages of 40 and 50 years. METHODS: Genomic DNA from family members was typed for alleles at known polymorphic genetic markers using polymerase chain reaction. Alleles were assigned to individuals, which allowed calculation of LOD scores using the programs Cyrillic (http://www.cyrillicsoftware.com) and MLINK (Cherwell Scientific Publishing LTD:, Oxford, UK). The genes for membrane glycoprotein (M6a) and chloride channel 3 (CLCN3) were analyzed by direct sequencing for mutations. RESULTS: A new locus for arRP (RP29) has been mapped to chromosome 4q32-q34. A maximum two-point LOD score of 3.76 was obtained for the marker D4S415, with no recombination. Two recombination events in the pedigree positioned this locus to a region flanked by markers D4S621 and D4S2417. A putative region of homozygosity by descent was observed between the loci D4S3035 and D4S2417, giving a probable disease interval of 4.6 cM. Mutation screening of two candidate genes, M6a and CLCN3, revealed no disease-associated mutations. CONCLUSIONS: The results suggest that the arRP phenotype maps to a new locus and is due to a mutated gene within the 4q32-q34 chromosomal region.     

中国北方一常染色体显性遗传先天性核性白内障家系CRYGD基因突变的鉴定

背景 先天性白内障是儿童致盲的主要原因之一,约1/3的先天性白内障由遗传因素引起,多为常染色体显性遗传,目前确定至少26个基因为常染色体显性遗传先天性白内障(ADCC)的致病基因,发现的致病基因突变已超过100种.目的 明确一ADCC家系的致病基因突变.方法 对2011年1月在北京同仁医院就诊的一来自河北的汉族ADCC家系进行分析,在获得受检者知情同意后,对所有家系成员进行详细的眼科检查并采集外周静脉血各5 ml,提取全基因组DNA.在已知的17个ADCC致病基因周围选取21个荧光标记的微卫星,经多重PCR扩增后进行连锁分析,两点法计算LOD值.对候选基因进行DNA直接测序分析,用ProtScale软件对基因突变前后蛋白局部的疏水性进行分析.用限制性片段长度多态性(RFLP)方法对所有家系成员及100个正常对照者进行基因突变共分离分析.结果 该家系共4代20名成员,其中患者9例,连续4代均有患者发病,符合常染色体显性遗传特征.临床检查证实9例患者均为双眼晶状体核性混浊.连锁分析发现微卫星D2S325和D2S2358与该家系中所有患者均连锁,重组分数(θ)为0时D2S325获得最大LOD值,为4.68.对位于D2S325附近的CRYGC和CR YGD基因进行DNA直接测序,发现CRYGD基因cDNA第127位一已知错义突变(c.T127C),导致编码蛋白第43位色氨酸变为精氨酸(p.W43R).ProtScale软件预测突变后的CRYGD蛋白第43位及其周围氨基酸疏水性明显增加.该突变与家系内所有患者表型共分离,家系中表型正常的成员及100名正常对照者均未发现此突变.结论 CRYGD基因c.T127C突变是该ADCC家系的致病基因突变,蛋白局部疏水性增加造成的空间结构异常可能是引起该ADCC家系发病的主要原因.     

A new locus for autosomal dominant cataract on chromosome 19: linkage analyses and screening of candidate genes

PURPOSE: To map and identify the mutated gene for autosomal dominant cataract (ADC) in family ADC4. METHODS: Ophthalmic evaluations were performed on an American family with ADC and a panel of polymorphic DNA sequence-tagged site (STS) markers for known ADC loci and other genome-wide polymorphic markers were used to map the gene; two-point lod scores were calculated. Fine mapping was undertaken in the chromosomal regions of maximum lod scores, and candidate genes were sequenced. RESULTS: A four-generation American family with ADC was studied. The only phakic individual exhibited white and vacuolated opacities in the cortical region. This ADC locus mapped to several suggestive chromosomal regions. Assuming full penetrance, the highest calculated maximum lod score was 3.91 with D19S903 [corrected] On chromosome 12, we sequenced all exons and the exon-intron borders of the membrane intrinsic protein (MIP) gene. On chromosome 19, all exons and the exon-intron borders of genes for lens intrinsic membrane2 (LIM2), ferritin light chain (FTL), and the human homologue of the Drosophila sine oculis homeobox 5 (SIX5) were sequenced, and the 3' untranslated repeat region (UTR) of the dystrophy (DMPK) gene and both the 5' and 3' UTRs of the SIX5 genes were amplified; the promoter for LIM2 was sequenced. For these genes, the sequence matched that in the reference libraries, and the DMPK gene had a normal number of CTG repeats. CONCLUSIONS: The mutated gene in ADC4 probably represents a new, not yet identified locus on chromosome 19. In one phakic member, the cortical cataracts were punctate and vacuolated.     

Identification of a novel locus on 2q for autosomal dominant high-grade myopia

PURPOSE: Myopia, or nearsightedness, is a visual disorder of high and growing prevalence in the United States and in other countries. Pathologic high myopia, or myopia of 相似文献   

先天性粉尘状白内障一家系基因突变定位

目的 探讨先天性粉尘状白内障一家系的基因突变定位.方法 回顾性研究.对一先天性白内障家系成员(共32人,其巾患者15人)散瞳后采用裂隙灯显微镜观察晶状体,并取外周血提取DNA样品.选取常染色体上微卫星标记物,通过聚合酶链反应(PCR)进行扩增后,进行基因扫描.利用GeneMapper软件进行PCR扩增产物片段大小和单体型分析.分别通过Linkage 5.1和GeneHunter软件进行两点法和多点法对数优势记分(LOD)值计算.对候选基因通过测序进行基因序列分析.结果 家系成员中的白内障患者晶状体环胎儿核可见散在的类似于蚁卵的短棒状混浊.在不同患者间以及同一患者的不同眼别存在晶状体混浊程度和形态的差异.两点法计算LOD值,在重组率(θ)为0时,微卫星位点D20S186、D230S163、D20S915、D20S152、D20S98、D20S904、D20S875、D20S112、D20S1140、D20S432均获得正值,其中在D20S904获得最大LOD值6.02.通过单体型构建,发现微卫星位点D20S163在Ⅳ7患者发生交换,而D20S912在Ⅱ3患者发生交换.基因序列分析未发现BFSP1、PLCB4基因突变.结论 该家系突变基因位于常染色体20p12.1-p11.23上微卫星位点D20S186和D20S912间5.47厘摩范围内.     

常染色体显性遗传性白内障一家系致病基因的研究

目的:对一个4代常染色体显性遗传先天性白内障家系进行致病基因研究。方法:对15例家系成员(8例患者,7例非患者)进行眼部检查,采集静脉血,提取基因组DNA,选取已报道的与常染色体显性遗传性白内障相关的19个位点附近的微卫星标记,PCR扩增后进行基因型分析,用连锁分析进行定位;对提示连锁的标记计算Lod值,并构建单体型;对定位区域内已知候选基因测序。结果:该家系患者表型为绕核性白内障;患者在17q11-12有共享基因型,该位点微卫星标记与致病基因间的两点连锁最大Lod值为2.71,证实该位点与该家系的致病基因连锁;测序未发现CRYBA1/BA3突变。结论:该家系的致病突变不是由于CRYBA1/A3外显子和调控区突变,可能是未被发现基因突变或机制参与该家系的发病。     

一个常染色体显性遗传先天性白内障家系致病基因筛查

目的: 对中国一个常染色体显性遗传先天性白内障家系(ADCC)的已知候选基因进行筛查以寻找致病位点。方法: 收集一个ADCC家系的临床资料并采集静脉血。在24个已知与ADCC相关基因附近选择微卫星标记,利用Linkage软件Mlink软件包进行连锁分析计算Lod值。结果: 此家系白内障类型为核性白内障,24个候选基因附近50个微卫星Lod值均小于0,微卫星所在区域与此家系致病基因无连锁关系。结论: 此ADCC家系致病基因不是已知的与ADCC相关基因,可能是一个新的致病基因突变导致此家系疾病发生。     

Genetically distinct autosomal dominant posterior polar cataract in a four-generation Japanese family

PURPOSE: To describe the clinical findings of a form of posterior polar cataract in a large Japanese family and to determine whether the posterior polar cataract is causally related to other autosomal dominant cataracts with known genes, chromosomal locations, or both. METHODS: Systemic and ocular histories were obtained and comprehensive ophthalmic examinations were performed in 15 of 37 members of the Japanese family. The posterior polar cataract was transmitted in an autosomal dominant manner through four generations. Although there is some variation in the degree of opacification, the posterior polar cataract in this family is characterized by progressive disk-shaped posterior subcapsular opacities. Genetic linkage analysis was performed with 41 polymorphic microsatellite markers located in chromosomal regions known for linkage to cataracts. Genomic DNA extracted from the 15 individuals was amplified by polymerase chain reaction, the genotype at the marker loci was determined in each family member, and the lod score was calculated at each locus. RESULTS: Significant linkage of the posterior polar cataract was ruled out from the following 10 loci or chromosomal regions: 16q22 and 1p36, to which two forms of autosomal dominant posterior polar cataract have been assigned: 1q21-q25, 2q33-q35, 13cen, 17p13, 17q11-q12, 17q24, 21q22, and 22q, which are the regions responsible for other autosomal dominant congenital cataracts. CONCLUSIONS: This study confirms the genetic heterogeneity of autosomal dominant posterior polar cataracts and demonstrates that the posterior polar cataract in this Japanese family is phenotypically and genetically distinct from previously mapped cataracts.     

A novel locus for autosomal dominant cone and cone-rod dystrophies maps to the 6p gene cluster of retinal dystrophies

PURPOSE: To characterize clinically and genetically a four-generation Italian family with autosomal dominant retinal dystrophy. METHODS: Thirty-seven family members underwent a detailed ophthalmologic investigation, comprising visual acuity determination, fundoscopy, electroretinogram, and electrooculogram. A genome-wide scan was performed, and three candidate genes mapping to the linked region were screened for mutations by direct sequencing. RESULTS: Nineteen individuals were affected by cone-rod dystrophy and four by cone dystrophy, whereas, in another subject, the diagnosis was compatible with central areolar choroidal dystrophy. The genome-wide search allowed mapping the disease locus to chromosome 6, region p12.2-p21.1, with a maximum lod score of 6.71. Analysis of key recombinants in affected individuals placed the locus to a 12-Mb region flanked by newly generated markers 6-41025 and 6-52969. Assuming complete penetrance, recombinations in two healthy individuals defined a smaller critical region of 3.7 Mb between markers 6-42153 and D6S459. Three genes mapping within the linked interval (RDS, GUCA1A, and GUCA1B) were considered excellent candidates because of their involvement in distinct forms of retinal dystrophies. However, mutation analyses of these genes failed to identify pathogenetic mutations. CONCLUSIONS: The significant lod scores obtained and the absence of mutations in RDS, GUCA1A, and GUCA1B support the existence of a novel, yet unidentified gene responsible for retinal dystrophy within the chromosome 6 cluster.     

A novel alphaB-crystallin mutation associated with autosomal dominant congenital lamellar cataract

PURPOSE: To identify the mutation and the underlying mechanism of cataractogenesis in a five-generation autosomal dominant congenital lamellar cataract family. METHODS: Nineteen mutation hot spots associated with autosomal dominant congenital cataract have been screened by PCR-based DNA sequencing. Recombinant wild-type and mutant human alphaB-crystallin were expressed in Escherichia coli and purified to homogeneity. The recombinant proteins were characterized by far UV circular dichroism, intrinsic tryptophan fluorescence, Bis-ANS fluorescence, multiangle light-scattering, and the measurement of chaperone activity. RESULTS: A novel missense mutation in the third exon of the alphaB-crystallin gene (CRYAB) was found to cosegregate with the disease phenotype in a five-generation autosomal dominant congenital lamellar cataract family. The single-base substitution (G-->A) results in the replacement of the aspartic acid residue by asparagine at codon 140. Far UV circular dichroism spectra indicated that the mutation did not significantly alter the secondary structure. However, intrinsic tryptophan fluorescence spectra and Bis-ANS fluorescence spectra indicated that the mutation resulted in alterations in tertiary and/or quaternary structures and surface hydrophobicity of alphaB-crystallin. Multiangle light-scattering measurement showed that the mutant alphaB-crystallin tended to aggregate into a larger complex than did the wild-type. The mutant alphaB-crystallin was more susceptible than wild-type to thermal denaturation. Furthermore, the mutant alphaB-crystallin not only lost its chaperone-like activity, it also behaved as a dominant negative which inhibited the chaperone-like activity of wild-type alphaB-crystallin. CONCLUSIONS: These data indicate that the altered tertiary and/or quaternary structures and the dominant negative effect of D140N mutant alphaB-crystallin underlie the molecular mechanism of cataractogenesis of this pedigree.     

CRYBA3/A1 gene mutation associated with suture-sparing autosomal dominant congenital nuclear cataract: a novel phenotype

PURPOSE: To identify the genetic defect leading to the congenital nuclear cataract affecting a large five-generation Swiss family. METHODS: Family history and clinical data were recorded. The phenotype was documented by both slit lamp and Scheimpflug photography. One cortical lens was evaluated by electron microscopy after cataract extraction. Lenticular phenotyping and genotyping were performed independently with short tandem repeat polymorphism. Linkage analysis was performed, and candidate genes were PCR amplified and screened for mutations on both strands using direct sequencing. RESULTS: Affected individuals had a congenital nuclear lactescent cataract in both eyes. Linkage was observed on chromosome 17 for DNA marker D17S1857 (lod score: 3.44 at theta = 0). Direct sequencing of CRYBA3/A1, which maps to the vicinity, revealed an in-frame 3-bp deletion in exon 4 (279delGAG). This mutation involved a deletion of glycine-91, cosegregated in all affected individuals, and was not observed in unaffected individuals or in 250 normal control subjects from the same ethnic background. Electron microscopy showed that cortical lens fiber morphology was normal. CONCLUSIONS: The DeltaG91 mutation in CRYBA3/A1 is associated with an autosomal dominant congenital nuclear lactescent cataract. A splice mutation (IVS3+1G/A) in this gene has been reported in a zonular cataract with sutural opacities. These results indicate phenotypic heterogeneity related to mutations in this gene.     

常染色体显性遗传先天性核性白内障一家系致病基因的初步定位

目的 初步定位一个显性遗传性先天性核性白内障家系的致病基因.方法 在已知与先天性白内障相关的致病基因附近选择合适的微卫星标记,基因组PCR扩增后进行基因分型,由LINKAGE软件处理,对该家系进行连锁分析.结果 在22q的D22S258、D22S315、D22S1163显示最大LOD值2.11（重组率θ=0）.单倍型分析提示致病基因位于D22S1174～D22S270大约18.5 Mbp的遗传距离.结论 该家系的致病基因定位于22q11.2～22q13,该范围内的CRYBB1、CRYBB2、CRYBB3、CRYBA4为其可能致病基因.