中国人一个显性视网膜色素变性家系8号染色体连锁分析

目的用连锁分析法对中国人一个显性视网膜色素变性家系8号染色体进行分析，确定致病基因。方法随机选取8号染色体RP1基因上下约10厘摩(cm)范围内的10对微卫星标记(marker)，确立单倍体型，用两点法计算最大优势对数(LOD SCORE)值。结果所选微卫星标记与该家系表型间最大LOD值小于1。结论RP1基因可能为该家系的非致病性基因，用连锁分析法进行致病基因排除对最终确立致病基因所在染色体的范围具有重要的价值。     

一个中国视网膜色素变性家系的RP3基因突变

目的 探讨一个中国视网膜色素变性(RP)家系的突变基因位点.方法 在获得知情同意后对该家系成员进行病史采集、眼部检查和病情追溯,绘制家系图,并对其中26例采血,进行DNA提取、聚合酶链反应、RP3基因外显子ORF15测序.结果 该家系共有成员57名,其中直系42名(含21例患者).患者表现为夜盲、近视、眼底色素沉着、血管细、视盘淡,视野向心性缩窄甚至呈管状,暗视视网膜电图(ERG)显示a波、b波振幅明显下降甚至记录不到.家系特点为男性患者的女儿全部患病、男性患者的母亲均是患者,符合X连锁显性遗传特征.经PCR反向测序,发现突变位点位于ORF15 1339delA.结论 该家系患者病变由RP3基因外显子ORF15 1339delA位点突变所致.     

视网膜色素变性显性遗传家系3号染色体连锁分析

目的：用连锁分析法对三个显性视网膜色素变性家系(CY、WN、ZH)3号染色体进行分析，确定致病基因。方法：随机选取3号染色体视紫红质(rhodopsin，RH0)基因上下约5厘摩(centimorgan cM)范围内的6对微卫星标记(marker)，确立单倍体型，用两点法计算最大优势对数(LOD SCORE)值。结果：所选微卫星标记与CY、WN家系表型间LOD值呈负相关关系，而ZH家系与位点D3S3606间LOD值为2．52。结论：RH0基因为CY、WN家系的非候选基因，RHO基因可能是家系ZF致病基因。     

原发性视网膜色素变性1家系

先证者　女　 45岁　夜盲 2 3年 ,近 3年视力明显下降 ,于 2 0 0 2年 12月 15日就诊。双眼视力均为 0 8,呈管状视野 ,晶体后囊轻度混浊。散瞳后见视乳头蜡黄 ,视网膜血管狭窄 ,以动脉明显 ,视网膜上见大量骨细胞样色素沉着 ,形状不规则。诊断 :双眼原发性视网膜色素变性、并发性白内障。先证者之妹　女　 43岁　夜盲 2 0年 ,近 1年均为视力下降 ,于 2 0 0 2年 12月 17日就诊。双眼视力均为 1 0 ,视野明显缩小 ,晶体后囊轻度混浊。散瞳后见视乳头蜡黄 ,视网膜血管狭窄 ,以动脉明显 ,视网膜上见大量骨细胞样色素沉着 ,形状不规则。诊断 :双眼…     

视网膜色素变性一家系

视网膜色素变性属于常染色体隐性遗传或性连锁隐性遗传。作者于2001年5月曾遇到双视网膜色素变性1家系,却属于X连锁显性遗传,现报道如下。先证者男35岁自幼夜间视物不清,今来本院眼科检查被确诊为双眼视网膜色素变性。体格检查发育正常、营养良好、心肺无异常、神经反射存在、病理反射未引出。血尿便常规,肝肾功能均正常,双眼视力均为0.5,不能矫正。双眼睑无肿胀,结角膜均正常,双瞳等大,同圆,直接、间接对光反射灵敏。视乳头色淡呈淡黄色,边界不清,视网膜血管变细,双眼视网膜赤道有骨细胞样色素沉着,本病无特殊治疗。III先证者之女8岁夜间…     

视网膜色素变性1基因在常染色体显性遗传视网膜色素变性家系中的突变分析

目的:研究常染色体显性遗传视网膜色素变性(autosomal dominant retinitis pigmentosa,ADRP)家系中视网膜色素变性1(retinitis pigmentosa-1,RP1)基因的突变特征及其在RP发病机制中的作用。方法:运用聚合酶链反应和直接测序方法,对6个ADRP家系的47例成员和50例对照者进行了RP1基因全编码区和邻近剪切位点的内含子区域序列突变的筛选与检测。运用单因素分析、多因素Logistic回归分析研究RP1基因点突变在RP发病中的作用。结果:ADRP家系成员和对照组RP1基因第4外显子上检测出2个变异位点。在1691和1725密码子存在杂合的两种类型的密码子(S1691P,Ser-Pro,TCT→CCT;Q1725Q,Gln-Gln,CAA→CAG)。ADRP家系成员中Ser-1691-Pro及Gln-1725-Gln位点突变率显著高于正常对照组(χ2=11.202,P<0.05)。结论:RP1基因Ser-1691-Pro及Gln-1725-Gln位点多态性可增高RP的危险性,具有潜在的致病性,考虑为ADRP家系的易感基因。     

视网膜色素变性合并近视家系的临床及遗传学研究

目的 探讨一个视网膜色素变性合并近视家系的临床表现及遗传学特征.方法 在获得知情同意后对该家系所有能够到场的成员进行病史采集和眼部体检(包括眼底镜检查),对疑患病成员进行视网膜功能和形态学检查,对已故的或不能到场的家系成员的眼病情况进行追溯,绘制家系图.家系共有57名成员,其中直系成员42名.结果 直系成员42名中含患者21例,患者临床表现为夜盲、近视、眼底色素沉着、血管细、视盘色淡,视野向心性缩窄甚至呈管状,暗适应视网膜电图显示a、b波振幅明显下降甚至熄灭.家系共5代,除第Ⅴ代外,Ⅰ-Ⅳ代各有1-11例患者,特点为男性患者的女儿全部患病、男性患者的母亲都是患者.结论 本家系为原发性视网膜色素变性合并近视家系,基本符合X连锁显性遗传规律.     

一个X-连锁隐性遗传视网膜色素变性家系的RPGR基因新突变

目的 研究X-连锁隐性遗传视网膜色素变性(RP)家系RPGR基因突变男性患者和女性携带者的临床表型.方法 家系调查研究.收集RP先证者及其家系资料,完善眼科检查,抽取现存77名家系成员和80名正常对照者外周静脉血,提取DNA,进行聚合酶链反应(PCR),扩增RPGR基因外显子ORF15,扩增产物纯化后直接测序.结果 RP家系中,8例RP患者均为男性,呈隔代传递,不存在男性至男性的传递,患者的母亲及女儿都是致病基因携带者而不发病,符合X-连锁隐性遗传方式.在8例男性RP患者和14例女性致病基因携带者的RPGR基因外显子ORF15+577_578位点发现一个AG缺失突变,引起阅读框架的改变,该基因缺失突变在家系中共分离.AG缺失突变导致男性患者典型的RP改变,但发病时间和进展程度不一.携带有杂合型基因突变的14例女性携带者最具特征性的临床表型是中高度近视眼(-5.00～-22.00 D).结论 该RP家系患者由RPGR 基因外显子ORF15移码突变致g.ORF15+577_578delAG位点缺失.RPGR基因外显子ORF15的新突变可导致男性患者严重的RP表型,但女性致病基因携带者仅表现为中高度近视眼.(中华眼科杂志,2011,47:516-520)

Abstract：

Objective To screen the mutation in the RPGR gene in a large Chinese family with X-linked recessive retinitis pigmentosa (RP) and to describe the phenotype in affected males and female carriers. Methods Ophthalmic examinations were performed in 77 family members of a RP pedigree to identify affected individuals. Polymerase chain reaction (PCR) and direct sequencing were used for screening of mutations in RPGR gene exon ORF15. Results Mutation screening demonstrated a novel mutation, g.ORF15+577_ 578delAG, which caused an open reading frameshift and resulted in premature truncation of the RPGR protein. This mutation was detected in 8 affected male individuals and 14 obligate female carriers in this family and was found to segregate with the phenotype in this family. This mutation led to a severe RP phenotype in male affected individuals with some variability in the age of onset of night blindness and loss of visual acuity, but was recessive in female carriers without a RP phenotype. However the most striking phenotypic feature in female carriers in this pedigree was moderate to high myopia with refractive error ranging from -5.00 D to -22.00 D in 14 female carriers. Conclusions This novel mutation in RPGR ORF15 causes serious RP phenotype in males and no RP phenotype in female carriers. Moderate to high myopia was a particular feature for female carriers in this pedigree. Our finding expands the spectrum of RPGR mutations causing RP and phenotypic spectrum of the disease in Chinese family, which is useful for further genetic consultation and genetic diagnosis.     

汉族常染色体显性视网膜色素变性一家系的连锁分析及突变筛查

背景 原发性视网膜色素变性(RP)有明显的遗传异质性和表型异质性,目前已确定的致病基因较多,确定患病家系的致病基因是进行基因治疗的基础. 目的 对患常染色体显性遗传性RP(ADRP)的一个汉族家系进行致病基因的定位和基因突变分析.方法 此家系的5代21名成员纳入研究,包括12例ADRP患者和9名表型正常者.12例患者进一步接受中心视野、间接检眼镜、眼电图(EOG)、视网膜电图(ERG)检查.对22个已知的ADRP致病基因所在染色体位点进行连锁分析,以确定该家系与疾病连锁的染色体区域,随后对该区域附近的候选基因视紫红质(RHO)进行直接测序评估其突变情况. 结果 间接检眼镜检查该家系先证者眼底表现符合原发性RP表现,EOG和ERG表现为波形记录不到,视野呈向心性缩小.两点连锁分析结果显示,该家系致病基因位点与遗传标记D3S1292连锁,在θ=0.0时得到最大优势对数(LOD)值为3.6671.候选的RHO基因直接测序结果发现,该家系所有患者第53位密码子的第2个核苷酸均出现了C→G的突变,致其氨基酸由脯氨酸变为精氨酸(Pro53Arg),而该家系正常成员中未发现此突变. 结论 RHO基因的错义突变Pro53Arg与RP疾病出现共分离现象,可确定为该ADRP家系的致病基因.     

A novel mutation of RPGR in a Chinese family with X-linked retinitis pigmentosa

AIM: To identify potential mutations and elucidate the clinical findings of male patients and female carriers of X-linked retinitis pigmentosa (XLRP) in a Chinese family. METHODS: A four generation pedigree was collected that consisted of 20 individuals. Genomic DNA was extracted from peripheral blood, and then the target fragments were amplified by PCR and sequenced directly. In addition, all affected patients and female carriers underwent comprehensively ophthalmic evaluation. RESULTS: A novel mutation c.2865G>A p.W955X in RPGR gene was identified of this family, including four affected individuals and eight carriers. All male patients, aging from 7 to 31y, tended to have more various, even potentially deleterious clinical features of RP. At the same time, individuals with heterozygous mutations (carriers) manifested a wide spectrum of clinical features. Herein, only two male patients and three female carriers manifested pathological myopia (PM). Among the female carriers, half of subjects who harbor poor visual acuity suffered esotropia or exotropia. Additionally, 16.7% and 66.7% of carriers had abnormal electroretinogram (ERG) and fundus, respectively. CONCLUSION: In this study, a novel mutation of the RPGR gene is identified, which broadens the spectrum of RPGR mutations, and elaborates the relationship between genotype and phenotype.     

X-连锁遗传视网膜色素变性相关基因研究概况

视网膜色素变性(retinitis pigmentosa,RP)是视网膜光感受器细胞和色素上皮细胞变性导致夜盲和进行性视野缺损的一组具有临床亚型的基因遗传性致盲眼底病。至今,X-连锁RP已定位6个致病基因,并克隆了2个基因(RP2和RP3)。本文对X连锁型RP的遗传基因研究进展予以综述。     

Optical coherence tomography and electro-oculogram abnormalities in X-linked retinitis pigmentosa

Purpose To determine the correlations between morphological optical coherence tomography (OCT) and electrophysiological electro-oculogram (EOG) alterations in families with X-linked retinitis pigmentosa (XLRP).Design Observational case series.Participants and Methods About 32 eyes of 16 members of four different families: Seven obligate carriers, four affected male homozygotes and five unaffected females underwent ophthalmologic completed exams including EOG and OCT. All the subjects were previously tested with genetic analysis. The results were statistically analysed.Results The abnormalities in OCT were detected in all carriers and affected males consisting of macular edema and increased RPE reflectivity compared to no alterations in unaffected females. The EOG was flat in all affected males; distinctly abnormal in eight eyes of obligate carriers; normal in two eyes of obligate carriers and in all unaffected females. In two obligate carriers, the EOG was not performed due to a nuclear cataract. The correlations between OCT and EOG alterations were statistically significant.Conclusions The OCT and EOG were demonstrated to be useful methods to identify the minimal alterations in carriers of X-linked retinitis pigmentosa.     

Phenotypic high myopia in X-linked retinitis pigmentosa secondary to a novel mutation in the RPGR gene

Background: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disease causing progressive degeneration of retinal photoreceptor cells. The most severe form of this disease is X-linked RP (XLRP), in which photoreceptor degeneration begins in early childhood and complete blindness often occurs by the fourth decade of life. Two genes commonly associated with XLRP have been previously identified.

Material and methods: One Spanish family with confirmed XLRP was studied for mutations using direct sequencing. A genotype-phenotype correlation with pathologic myopia (PM) is detailed.

Results: A new pathogenic mutation in the third exon of the RP GTPase regulator (RPGR) was identified: a variant c212C>G (pSER71*). This mutation appears as a hemizygous variant in the male proband with RP, and as heterozygous variant in the females of this pedigree who invariably exhibit symmetrical PM in both eyes.

Conclusion: A complete family history allowed determination of the inheritance pattern providing genetic counseling for patients and their families. The geno-phenotypic attributes of this heterozygosity suggest a correlation between RP and PM. This novel mutation would expand the mutation spectrum of RP2 and RPGR, and help to study molecular pathogenesis of RP.     

Novel RPGR mutations with distinct retinitis pigmentosa phenotypes in French-Canadian families

PURPOSE: To characterize the molecular defects in two x-linked retinitis pigmentosa (RP) families. We hypothesized that different RPGR mutations result in distinct RP phenotypes. DESIGN: Observational case series. METHODS: Fifteen members in family I and three members in family II were evaluated. Full ophthalmic evaluations were done. Linkage analyses were performed and likelihood of odds scores (LOD score) were calculated. For mutation analyses, we used dHPLC and automated sequencing. RESULTS: Two novel RPGR mutations were identified in the two families; a Glu 414 (2-bp del) frameshift mutation in family I and an IVS 2-1 (g to a) splice site mutation in family II. All male family members in family I were severely affected by RP but maintained central visual acuities until their 50s and did not develop a bull's eye maculopathy. The female phenotype was highly variable. Some of the carriers exhibited a severe phenotype, one female displayed an asymmetric phenotype, and other carriers were asymptomatic. All members with the RPGR frameshift mutation exhibited rod-cone electroretinograms abnormalities, whereas five members had hearing loss. Male members of family II were severely affected, with early visual acuity loss, central scotomas, and bull's eye maculopathy. The female family members were asymptomatic but displayed cone-rod electroretinograms changes. There was no hearing loss. CONCLUSIONS: Different RPGR mutations lead to distinct RP phenotypes, with a highly variable inter- and intrafamilial phenotypic spectrum of disease that is associated with the type of mutation in RPGR and nonrandom X chromosome inactivation, respectively.