常染色体显性遗传视网膜色素变性致病基因的研究进展

视网膜色素变性（retinitis pigmentosa,RP)是常见的遗传性视网膜变性疾病，它具有高度的遗传异质性，有不同的遗传方式和临床表型，目前已发现常染色体显性遗传型视网膜色素变性（autosomal dominant retinitis pigmentosa,ADRP)的12种基因，其中已被克隆的有RHO，RDS，ROM1，RP1，NRL及CRX，未被克隆的有RP9，RP10，RP11，RP13，RP17及RP18，本文主要介绍与ADRP相关的几个基因的最新研究进展。     

常染色体显性遗传视网膜色素变性的相关基因研究概况

视网膜色素变性(retinitispigmentosa,RP)是一种发病机制尚未完全明确的遗传性疾病,其在遗传和表型上具有较大的异质性。其中常染色体显性遗传视网膜色素变性(autosomadominantretinitpigmentosa,ADRP)占RP的20%～25%,目前发现至少有19个致病基因,其中11个已被克隆。本文将就ADRP的相关致病基因的研究进展作一综述。     

常染色体显性遗传视网膜色素变性患者视紫红质基因和视网膜变性慢基因突变检测分析

视网膜色素变性(RP)是一组常见的视网膜感光细胞和色素上皮细胞变性导致夜盲和进行性视野缺损的遗传性眼底病,其发病机制尚未完全明确.RP具有高度的遗传异质性,其遗传方式非常复杂,分为常染色体显性遗传(ADRP)、常染色体隐性遗传(ARRP)、X-连锁遗传(XLRP)和双基因型遗传(Digenic RP),最近报道还有线粒体遗传方式(mitochondrial RP)[1].视紫红质基因(RHO)是最早被识别的RP基因,在ADRP中发病率占30%～40%[2],而盘膜周边蛋白/视网膜变性慢基因(peripherin/RDS)在ADRP中占5%[3].我们对13个ADRP家系进行了RHO和视网膜变性慢基因(RDS)检测分析,观察其突变特征,现将其结果报道如下.     

视网膜色素变性的相关基因研究进展

视网膜色素变性(RP)是由于视网膜感光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种常见的、遗传性、致盲性眼底病,具有较大的临床和遗传异质性。迄今通过连锁分析和侯选基因筛查,已有14个常染色体显性遗传ADRP;20个常染色体隐性遗传ARRP和5个X-染色体连锁遗传型XLRP位点被定位,其中32个基因已被克隆,每种遗传方式都有多个基因被克隆。对于这些致病基因的结构、突变及其功能目前已经有了新的研究进展。     

常染色体显性遗传视网膜色素变性基因检测研究进展

视网膜色素变性(RP)是一组进行性的可致肓的遗传性视网膜疾病,以视网膜光感受器和色素上皮细胞变性为主要特征,发病率约为1/4000,全世界受累人数约为1百万人.RP具有明显的临床和遗传异质性.常染色体显性遗传视网膜色素变性(ADRP)占RP的20％～25％,目前共定位了21个位点,其中克隆了19个基因.由于ADRP危害较为严重、发病率较高,近年来已成为眼科遗传学研究的热点.此文对近年来研究进展做一综述.     

IMPDH1基因突变与视网膜色素变性的研究进展

视网膜色素变性(RP)是视网膜感光细胞和色素上皮细胞变性导致的最常见的遗传性致盲眼底病,具有高度的遗传异质性及临床异质性。IMPDH1存在于全身各处器官中。近年来对RP发病机制的探讨已成为研究热点。随着对IMPDH1基因研究的深入,人们发现IMPDH1基因对RP的发病机制研究有着重要意义。对于这种致病基因的结构、突变及其功能目前已有了新的研究进展。本文综述了IMPDH1基因在视网膜色素变性中的最新研究进展。     

一视紫红质基因突变常染色体显性遗传视网膜色素变性家系的临床特征及其与基因型的关系

视网膜色素变性(RP)是以夜盲、进行性视野损害、视网膜色素沉着、视盘呈蜡黄色萎缩和视网膜电图(ERG)呈熄灭型为主要临床特征的遗传性致盲眼病[1,2].RP遗传方式复杂,以常染色体显性遗传RP(ADRP)为多见[3].在已成功克隆出15个ADRP致病基因中,视紫红质(RHO)基因是引起ADRP的主要致病基因,大约20%的ADRP患者存在RHO基因突变[4-6].RHO突变位点很多,表型各异.为探讨RHO基因型与RP的关系,我们观察了1个RHO基因突变的ADRP家系中RP患者的临床特征.现将结果报道如下.     

视网膜色素变性分子遗传学研究现状

视网膜色素变性是由于视网膜感光细胞和色素上皮细胞变性导致夜盲和进行性视野缺损的最常见的遗传性眼底病 ,具有大的临床和遗传异质性。其遗传方式可为常染色体显性、常染色体隐性、X染色体连锁遗传和散发型。目前已发现RP相关基因 1 4种 ,其中常染色体显性遗传 4种 ,常染色体隐性遗传 8种 (包括视紫质 ) ,X染色体连锁遗传 2种。本文着重阐述了已知RP相关基因的研究现状。     

视网膜色素变性分子遗传学研究现状

视网膜色素变性是由于视网膜感光细胞和色素上皮细胞变性导致夜盲和进行性视野缺损的最常见的遗传性眼底病，具有大的临床和遗传异质性。其遗传方式可为常染色体显性、常染色体隐性、Ｘ染色体连锁遗传和散发型。目前已发现ＲＰ相关基因１４种，其中常染色体显性遗传４种，常染色体隐性遗传８种（包括视紫质），Ｘ染色体连锁遗传２种，本文着重阐述了已知ＲＰ相关基因的研究现状。     

原发性视网膜色素变性一家系

视网膜色素变性（RP）是临床上常见的眼底疑难病，原发性视网膜色素变性是一种以进行性感光细胞及色素上皮功能丧失为共同表现的遗传性视网膜变性疾病，有遗传异质性。现将我院眼科发现的一个包括8例患的遗传家系报道如下。     

A new Leu253Arg mutation in the RP2 gene in a Japanese family with X-linked retinitis pigmentosa

PURPOSE: To identify the clinical findings in a Japanese family with X-linked retinitis pigmentosa associated with mutation in codon 253 (Leu253Arg) in the RP2 gene. METHODS: Case reports included clinical features and results of fluorescein angiography, electroretinogram, kinetic visual field testing, and DNA analysis. Two affected hemizygotes with retinitis pigmentosa associated with transversion mutations in codon 253 (Leu253Arg) of the RP2 gene and the obligate carriers were examined. RESULTS: A novel Leu253Arg mutation of the RP2 gene was found to cosegregate with retinal degeneration in two affected males and two carriers in female heterozygote in a Japanese family. The ophthalmic findings in hemizygote showed severe retinal degeneration. In the obligate carrier, mild chorioretinal degeneration was observed in both eyes but a tapetal-like reflex of the fundus was not apparent. CONCLUSIONS: The mutation at codon 253 of the RP2 gene is the first mutation reported in a Japanese family. It is concluded that the mutation of the RP2 gene also causes the X-linked retinitis pigmentosa in Japanese patients.     

The 208delG mutation in FSCN2 does not associate with retinal degeneration in Chinese individuals

PURPOSE: The 208delG (c.72delG, p.Thr25GlnfsX120) mutation in the FSCN2 gene was reported to cause autosomal dominant retinitis pigmentosa (ADRP) and autosomal dominant macular degeneration (ADMD). The purpose of this study was to detect the 208delG mutation in Chinese individuals, with or without hereditary retinal degeneration. METHODS: DNA fragments encompassing the 208delG mutation were amplified by polymerase chain reaction (PCR). The amplicons were analyzed by sequencing or/and heteroduplex- single-strand conformational polymorphism (SSCP) analysis. An ophthalmic evaluation was conducted in those individuals with the 208delG mutation. RESULTS: The 208delG mutation was detected in 8 of 242 unrelated probands: 175 with retinitis pigmentosa (RP), 20 with Leber congenital amaurosis (LCA), and 47 with cone-rod dystrophy (CORD). Of the eight, the retinal diseases were RP in six probands, LCA in one proband, and CORD in one proband. The disease was transmitted as an autosomal dominant (one family), autosomal recessive (two families), or sporadic (five families) trait. The mutation did not cosegregate with retinal degeneration in three families, whereas five normal family members also had the mutation. In addition, this mutation was also detected in 13 of 521 unrelated control subjects. CONCLUSIONS: The 208delG mutation in FSCN2 is not associated with hereditary retinal degeneration in the Chinese individuals examined, which contradicts the original report about mutation in FSCN2 as a cause of ADRP and ADMD. This finding reminds us that great care is needed in making mutation-disease associations.     

Phenotypic intrafamilial variability associated with S212G mutation in the RDS/peripherin gene

PURPOSE: To describe an Italian family in which two separate phenotypes (retinitis pigmentosa and adult onset vitelliform macular dystrophy) are associated with an identical mutation (S212G) in the peripherin/RDS gene. This mutation has already been reported in patients with retinitis pigmentosa, but it has never been previously detected in association with adult onset vitelliform macular dystrophy. METHODS: A 38-year-old woman complained of bilateral mild metamorphopsias and on ophthalmologic examination she showed the clinical phenotype of adult onset vitelliform macular dystrophy. Her 62-year-old mother was clinically diagnosed with a retinitis pigmentosa, with a severe clinical course. RESULTS: In both patients, molecular genetic analysis revealed a 874A-->G transition in the exon 2 of the RDS gene leading to the amino acid change of S212G. CONCLUSIONS: Peripherin/RDS S212G mutation may have damaging effects on the formation and stability of the photoreceptors' disk structure and may be associated with different clinical phenotypes, even in the same family. Intrafamilial phenotypic variability has been reported for other RDS mutations; this supports the possible influence of modifier genes or environmental factors in the clinical expression of RDS gene variants. Moreover, it suggests that in patients with retinal degeneration and peripherin/RDS mutation, caution should be taken both in using molecular genetic results to predict the clinical course of the disease and in offering genetic counseling.     

Genotype-phenotype correlation of mouse pde6b mutations

PURPOSE: To identify the underlying molecular defects causing retinal degeneration in seven N-ethyl-N-nitrosourea (ENU) induced mutant alleles of the Pde6b gene and to analyze the timescale of retinal degeneration in these new models of retinitis pigmentosa. METHODS: Conformation sensitive capillary electrophoresis and DNA sequencing were used to identify the mutations in the Pde6b gene. Visual acuity testing was performed with a visual-tracking drum at ages ranging from postnatal day 25 to week 10. Retinal examination was performed with an indirect ophthalmoscope. Animals were killed and eyes were prepared for histologic analysis. RESULTS: Point mutations in the seven new alleles of Pde6b were identified: Three generated premature stop codons, two were missense mutations, and two were splice mutations. The three stop codon mutants and one of the splice mutants had phenotypes indistinguishable from the Pde6b(rd1) mouse in rapidity of onset of retinal degeneration, suggesting that they are null alleles. However, the remaining alleles showed slower onset of retinal degeneration, as determined by visual acuity testing, fundus examination, and histology, indicating that they are hypomorphic alleles. CONCLUSIONS: These data demonstrate a correlation between genotype and phenotype. Four of the mutants with severe genetic lesions have rapid onset of retinal degeneration, as determined by fundus examination. These mice were indistinguishable from Pde6b(rd1) mice, which are effectively blind by 3 weeks of age. In contrast, the milder genetic lesions show a slower progression of the disease and provide the community with models that more closely mimic human retinitis pigmentosa.     

Histopathologic study of variation in severity of retinitis pigmentosa due to the dominant rhodopsin mutation Pro23His

PURPOSE: To compare histopathologic findings in an autopsy eye of an 87-year-old woman with retinitis pigmentosa and the rhodopsin mutation Pro23His with findings in an autopsy eye of a 77-year-old female relative (first cousin) with retinitis pigmentosa and the same mutation. DESIGN: Histopathologic study. METHODS: One eye from each patient was prepared for light and electron microscopy within 5 hours after death. Photoreceptor nuclear counts were performed. RESULTS: Photoreceptor degeneration and intraretinal bone spicule pigmentation were evident in both cases. The younger patient had more extensive photoreceptor loss and more intraretinal pigmentation than her older relative. CONCLUSION: A marked variation in the extent of retinal degeneration can be seen in two relatives with retinitis pigmentosa and rhodopsin, Pro23His. This study supports the idea that factors other than the primary gene defect are responsible for the severity of this condition.     

A Swedish family with a mutation in the peripherin/RDS gene (Arg-172-Trp) associated with a progressive retinal degeneration

Purpose: To clinically characterize a Swedish family with autosomal dominant retinitis pigmentosa due to a mutation, Arg-172-Trp, in the peripherin/RDS gene. Methods: Full clinical evaluation including kinetic visual field testing, measurement of dark-adaptation threshold, and full-field electroretinography in seven patients with autosomal dominant retinitis pigmentosa and three healthy family members. Denaturing gradient gel electrophoresis (DGGE) was used for mutation screening in seven patients and six healthy members of the family. Results: Three of four siblings from the middle generation and four of the younger generation were heterozygous for the peripherin/RDS Arg-172-Trp mutation. The mutation segregated with the disease. Visual acuity decreased progressively with age and visual fields were moderately constricted in young patients, while central scotoma and constriction of the fields were detected in the family members above 50 years of age. The results from full-field electrography were comparable with a widespread retinal degeneration. Conclusions: Earlier, the peripherin/RDS Arg-172-Trp mutation was associated primarily with a macular degeneration phenotype. One previous study indicated that this mutation also can give rise to a degeneration of the more peripheral parts of the retina. In the present study, a widespread retinal degeneration is seen in the patients above 50 years of age, carrying the Arg-172-Trp mutation.     

Intrafamilial phenotypic variability in families with RDS mutations: exclusion of ROM1 as a genetic modifier for those with retinitis pigmentosa

OBJECTIVES: To identify suspected RDS mutations in families in which different people have been identified with either generalised retinal dystrophy or macular dystrophy. METHODS: Two families with a retinal dystrophy were extensively phenotyped and blood was taken for mutation analysis of the RDS (all) and ROM1 (retinitis pigmentosa patients only) genes. RESULTS: A novel p.Trp94X mutation in RDS was found in all three affected members of a two-generation family that was associated with retinitis pigmentosa in the son, pattern dystrophy in the daughter and fundus flavimaculatus in the mother. In the second family, the proband with retinitis pigmentosa carried a p.Arg220Trp mutation. The mother, who was unavailable for mutation screening, had adult vitelliform macular dystrophy. No ROM1 mutations were found in those with retinitis pigmentosa in either family. CONCLUSION: Mutations in RDS can be associated with an intrafamilial variation in retinal disease. The phenotypes range from Stargardt-like macular dystrophy to classic retinitis pigmentosa. Clinical relevance: Intrafamilial phenotypic variation may be due to the presence of environmental or genetic modifying factors. The presence of a modifying-sequence change in the coding region of ROM1 for two people with retinitis pigmentosa from two families with intrafamilial variation in RDS mutation phenotype has been excluded in this study.     

视网膜色素变性发病机制及治疗进展

视网膜色素变性（retintis pigmentosa,RP）是指以进行性感光细胞及色素上皮功能丧失为共同表现的遗传性、退行性的疾病,RP是主要的致盲性眼病。其遗传方式包括X连锁遗传、常染色体隐性或者显性遗传,也有散发。临床表现为典型的三联征:骨细胞样色素沉着、视网膜血管缩窄和视盘蜡样苍白。RP具有高度的基因异质性(多个突变位点引起同一疾病）及表型异质性。本文对RP的发病机制和治疗方法进行简要综述。     

Late-onset central areolar choroidal dystrophy caused by a heterozygous frame-shift mutation affecting codon 307 of the peripherin/RDS gene

Mutations in the peripherin/RDS gene have been identified in families with various retinopathies including those affecting primarily the macula and those restricted to the retinal periphery. Here, we describe the clinical findings of two sisters with late-onset central areolar choroidal dystrophy (CACD). The two siblings underwent genetic testing and were found to be carriers of a heterozygous frame-shift mutation 920delT affecting codon 307 of the peripherin/RDS gene and resulting in a truncated, likely functionless, protein with an altered C-terminus (Leu307fsX83). The identical mutation has previously been reported to cause slowly progressive autosomal dominant retinitis pigmentosa. In our two patients, the Leu307fsX83 mutation accounts for an unusually mild form of retinal degeneration.     

Late-Onset Central Areolar Choroidal Dystrophy Caused by a Heterozygous Frame-Shift Mutation Affecting Codon 307 of the Peripherin/RDS Gene

Mutations in the peripherin/RDS gene have been identified in families with various retinopathies including those affecting primarily the macula and those restricted to the retinal periphery. Here, we describe the clinical findings of two sisters with late-onset central areolar choroidal dystrophy (CACD). The two siblings underwent genetic testing and were found to be carriers of a heterozygous frame-shift mutation 920delT affecting codon 307 of the peripherin/RDS gene and resulting in a truncated, likely functionless, protein with an altered C-terminus (Leu307fsX83). The identical mutation has previously been reported to cause slowly progressive autosomal dominant retinitis pigmentosa. In our two patients, the Leu307fsX83 mutation accounts for an unusually mild form of retinal degeneration.