Multicenter genetic study of retinitis pigmentosa in Japan: I. Genetic heterogeneity in typical retinitis pigmentosa

A nationwide, multicenter study of typical retinitis pigmentosa (RP) was carried out in collaboration with 18 hospitals throughout Japan to obtain current information for genetic counseling. We analyzed the genetic heterogeneity of RP based on the parental consanguinity of 434 probands registered during a 6-month period in 1990. A gradual decline in the frequency of consanguineous marriage was recognized among the normal parents of RP patients. The relative frequencies of inheritance patterns were estimated as: autosomal recessive, 25.2%; autosomal dominant, 16.9%; X-linked, 1.6%; and simplex, 56.3%. A comparison of these results with previous reports in Japan revealed a decline in the relative frequency of autosomal recessive cases and an increase in simplex cases. This suggests a decrease in the incidence of autosomal recessive retinitis pigmentosa in Japan, as well as the necessity for exhaustive investigations aimed at identifying inheritance patterns for RP patients seeking genetic counseling.     

常染色体隐性遗传视网膜色素变性的相关基因研究进展

视网膜色素变性(rentinitis pigmentosa，RP)是一种发病机制尚未完全明确的遗传性致盲性视网膜疾病，特征性表现为夜盲、进行性视野缩窄和视力下降，眼底可见骨细胞样色素沉着、视网膜血管变细和视盘蜡黄三联症。RP具有较大的遗传异质性和临床异质性，其中常染色体隐性遗传视网膜色素变性(autosomal recessive RP，ARRP)占RP的5%～20%，目前已定位43个致病基因，克隆了其中40个，并且不断有新的相关致病基因被报道。本文就近3a发现与ARRP相关的AGBL5、ARHGEF18、HGSNAT和ZNF408四个基因研究进展作一综述。     

An epidemiogenetic study of typical retinitis pigmentosa in Japan--a preliminary report of nationwide, multicenter study]

We performed a nationwide, multicenter study of typical retinitis pigmentosa with reference to the inheritance patterns of the disease. A total of 253 probands were registered during two months of 1989, and an analysis of the parental consanguinity of 182 probands with the method of inbreeding coefficient enabled us to estimate the relative prevalence of genetic types; autosomal recessive trait: 47.6%; autosomal dominant trait: 17.3%; sporadic cases: 34.6%. A comparison of the results with previous studies has indicated a decrease in the prevalence of the autosomal recessive trait and an increase in the sporadic cases, as would be expected from the decrease in consanguineous marriages and offsprings in the past few decades in Japan. X-linked retinitis pigmentosa was rarely identified, but precise evaluation of its frequency needs further investigation.     

Mutation of human retinal fascin gene (FSCN2) causes autosomal dominant retinitis pigmentosa

PURPOSE: To characterize the clinical features of 14 Japanese patients with autosomal dominant retinitis pigmentosa (ADRP) who were found to have a mutation in the FSCN2 gene. METHODS: Mutation screening by single-strand conformation polymorphism (SSCP) was performed in 120 unrelated patients with ADRP, 200 unrelated patients with autosomal recessive retinitis pigmentosa (ARRP), and 100 patients with simplex RP (SRP). The DNA fragment that showed abnormal mobility on SSCP was sequenced. The clinical features of these patients were determined by visual acuity, slit lamp biomicroscopy, electroretinography, fluorescein angiography, and kinetic visual field testing. RESULTS: A novel 208delG mutation in the FSCN2 gene was identified in 14 patients from four unrelated families with ADRP. The ophthalmic findings were typical of RP. CONCLUSIONS: The findings show that a 208delG mutation in the FSCN2 gene produces ADRP. This mutation was found in 3.3% of the patients with ADRP in Japan, which suggests that it may be relatively common in Japanese patients with ADRP.     

Correlation between Goldmann perimetry and maximal electroretinogram response in retinitis pigmentosa

To evaluate the relationship between Goldmann perimetry and maximal electroretinographic responses in patients with retinitis pigmentosa, analyses were performed on 220 affected subjects and separately on two subgroups with autosomal dominant (n = 35) and autosomal recessive (n = 29) inheritance. Electroretinograms were recorded averaging 100 iterations elicited with a 20-lux/s, 0.5-Hz white flash ganzfeld stimulation. The peripheral isopters of the visual fields were delimited with I4e, IIIe and V4e targets, measured on conventional perimetry charts with a light pen and expressed in square centimeters. Unlike most previously published reports, this investigation showed a definite correlation (p = 0.0001) between maximal electroretinographic response amplitude and visual field areas. This correlation was more evident for I4e and IIIe isopters (r = 0.89 and 0.87, respectively) than for V4e isopter (r = 0.69). This phenomenon appears to be related to distortion occurring on standard isometric charts and to spatial summation effects in the peripheral field. Such correlations held for both the autosomal dominant and autosomal recessive subgroups. It appears that, if enough accuracy is provided, maximal electroretinographic responses and Goldmann visual fields are both good measures of the remaining functioning retina in nonsyndromic retinitis pigmentosa, irrespective of inheritance models and dystrophic patterns.Abbreviations ADRP autosomal dominant retinitis pigmentosa - ARRP autosomal recessive retinitis pigmentosa - RP retinitis pigmentosa - VF visual field     

Prevalence of posterior subcapsular lens opacities in patients with retinitis pigmentosa.

We clinically evaluated 338 patients with various genetic types of retinitis pigmentosa (RP) for the presence of posterior subscapsular (PSC) lens opacities. Of these, 180 (53%) had PSC lens changes or were bilaterally aphakic. Patients with X-linked recessive RP showed a greater prevalence and patients with autosomal dominant RP a lesser prevalence of PSC lens changes compared with autosomal recessive or isolated cases.     

HLA typing in retinitis pigmentosa.

HLA serological typing was performed on 173 patients with retinitis pigmentosa (RP) of all hereditary types. No significant difference was found in the frequency of any HLA (A, B, C) antigen, when comparing autosomal dominant and recessive RP patients with a control population.     

Evaluation of RLBP1 in 50 autosomal recessive retinitis pigmentosa and 4 retinitis punctata albescens Spanish families

Defects in retinal vitamin A metabolism or in genes expressed in the retinal pigment epithelium (RPE) are related to nonsyndromic retinitis pigmentosa (RP). The RLBP1 gene encodes the cellular retinaldehyde-binding protein which, in the RPE and Müller cells of the retina, is thought to play a role in retinoid metabolism and visual pigment regeneration. We describe a study of the involvement of the RLBP1 gene in 50 autosomal recessive retinitis pigmentosa (ARRP) and four retinitis punctata albescens Spanish families. Cosegregation and homozygosity studies using an intragenic polymorphism and three close markers (D15S116, D15S127, and D15S130) ruled out RLBP1 as the cause of ARRP in 26 pedigrees. In the remaining families, SSCP analysis of the coding region and sequencing of the abnormal migrating bands did not detect any disease-causing mutation. These results indicate that mutations in the RLBP1 gene are not responsible for the ARRP or retinitis punctata albescens in this set of Spanish families. We did, however, identify two frequent polymorphisms (3'UTR + 167 G > T, T: 0.23 and G: 0.77; IVS6 + 20 T > C, T: 0.36 and C: 0.64), a silent substitution (S218S), and a rare variant (5'UTR-101 G > A).     

视网膜色素变性与基因突变

视网膜色素变性 (RP)是常见的致盲性遗传疾病 ,目前已发现有数十个基因的 15 0多个突变位点与其有关。与常染色体显性遗传、常染色体隐性遗传和性连锁遗传相对应的最常见的突变基因分别是视红紫质基因、杆体环鸟苷酸磷酸二脂酶基因和三磷酸鸟苷酸酶调节因子基因 ,其他的突变基因还有盘膜边缘蛋白基因 (常染色体显性遗传 )、杆体环鸟苷酸离子通道基因、RPE6 5基因、视黄醛结合蛋白基因和酪氨酸激酶受体基因 (常染色体隐性遗传 ) ,RP2基因(性连锁遗传 ) ,线粒体DNA细胞色素b基因等 ,每个突变基因对应于人群中不同的RP患者。基因治疗将成为治疗RP的根本方法 ,而对RP突变基因的定位、基因的生物学功能、突变所造成的分子病理机制的深入认识 ,是进行基因治疗的关键。     

Genetic features of retinitis pigmentosa in Turkey

Sixty-two cases with retinitis pigmentosa from 42 index families were investigated to reveal the genetic features of the disease in Turkey. There were 42 propositi of whom 5 had a systemic syndrome associated with retinitis pigmentosa. Of the remaining 37 cases the condition was autosomal recessive in 21 (56.8%), sporadic in 12 (32.4%), autosomal dominant in 3 (8.1%) and X-linked recessive in one (2.7%). Sporadic cases may be more frequent as many hereditary cases are not brought to medical attention in rural families. Male preponderance among sporadic cases may indicate that there may be more X-linked cases. Nine out of 21 cases initially classified as sporadic displayed parental consanguinity and they were included as having autosomal recessive trait. Large families with autosomal recessive inheritance may prove valuable in linkage analysis and in defining future gene abnormalities.     

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。     

Fuchs' heterochromic cyclitis associated with retinitis pigmentosa: a family study.

To determine the hereditary, clinical histopathological aspects of the association between Fuchs' heterochromic cyclitis (FHC) and retinitis pigmentosa (RP), the family of a patient with FHC and bilateral RP was studied genealogically, ophthalmologically and immunogenetically. The oldest brother and the youngest sister of the proband had bilateral RP and glaucoma which in the brother lead to enucleation of an eye which was studied histologically. The proband, his brother with RP, and 2 of their healthy siblings were homozygous for the haplotype A3, B7, w6. The parents of the siblings were healthy, and the pedigree showed much parental consanguinity and indicated autosomal recessive inheritance of RP.     

常染色体隐性遗传视网膜色素变性家系视紫红质基因突变的检测分析

目的 观察一个近亲婚配常染色体隐性遗传视网膜色素变性（ARRP）家系中视紫红质基因（RHO）的突变特征，并探讨其视网膜色素变性(RP)发病机制。 方法 抽取8例该ARRP家系成员及10例正常对照者的外周静脉血5~8 ml；提取基因组DNA；采用聚合酶链反应（PCR）方法扩增RHO基因第1~5外显子和第1内含子基因 片段 ，用直接DNA测序法筛查RHO基因突变。 结果 来自同一家系3例患者RHO 基因的第5外显子第344密码子发生了A→G碱基的错义突变，导致了谷氨酰胺变成了精氨酸(G ln344Arg)，3例患者为该突变的纯合子。患者近亲婚配父母及1例未患病家庭成员为该突变 的杂合子。2例未患病家庭成员及10例正常对照者均未发现RHO基因突变。 结论 Gln344Arg突变可能是该ARRP家系的致病原因；在近亲婚配ARRP家系中RHO基因突变频率可能增加。 （中华眼底病杂志，2004，20：145-148）     

The empirical risk of retinitis pigmentosa in Japan]

The empirical risk of hereditary retinitis pigmentosa (RP), was studied based on a survey of the data from 378 families with RP who were seen in Juntendo University hospital from 1980 to 1988. If the cases have had affected sibling, the empirical risk is 19% for the other siblings, and 29% if they have parental consanguinity. Moreover the risk for male siblings is about 1.7 times higher than for female siblings. The prevalence in the general population of carriers with autosomal recessive hereditary RP was calculated to be about 0.8 to 1.7 in 100 persons. If a hereditary RP case marries a normal and unrelated partner, the risk is 0.4-0.9% for their child. If a case has many affected relatives (parents, grandparents, uncles or aunt etc), the risk is 24% for a son, and 30% for a daughter. Some normal persons among autosomal dominant families with incomplete penetrance are suspected to be carriers. The rate of penetration of the autosomal dominant gene was estimated to be 0.54. Therefore, the risk is 8.6% for the children of such persons. If the carriers are among X-linked families, the risk is 36% for their son. The risk is 1% or more for children of sporadic cases.     

宁夏地区137例原发性视网膜色素变性的遗传类型及临床表型分析

目的 分析宁夏地区137例原发性视网膜色素变性(RP)的遗传类型及临床表型。方法 137例确诊的RP患者纳入研究。所有患者均经过详细的家系调查以及视力、验光、直接或间接检眼镜、视野、光相干断层扫描(OCT)和视网膜电图等全面的眼科检查。根据家族史及眼底表现进行分型;结合视力、OCT检查结果进行临床特点分析。结果 137例中55例患者有明确家族史,82例为散发型患者。55例患者中29例为常染色体显性遗传(AD)RP,16例为常染色体隐性遗传(AR) RP,10例为X-连锁遗传(XL)RP。有明确家族史及散发的108个家系中,ADRP 8个家系,占7.4％;ARRP 15个家系,占13.9％;XLRP 3个家系,占2.8％;散发型RP 82个家系,占75.9％。其中,15个为近亲结婚家系,占有明确家族史的26个家系的57.7％。患者年龄6～70岁。根据眼底表现分为典型RP和非典型RP。前者102例,占74.5％;后者35例,占25.5％。所有ADRP患者和XLRP患者均表现为典型RP;在ARRP患者中,10例表现为典型RP,占62.5％,6例为非典型RP,占37.5％;散发型RP患者中,53例表现为典型RP,占64.6％,29例为非典型RP,占35.4％。非典型RP患者中,17例为无色素型RP,占48.6％。3例年幼的无色素型RP均被误诊为弱视。最小视角对数(logMAR)最佳矫正视力：ADRP患者≥51岁组平均为1.04±0.51;ARRP和XLRP患者21～30岁组,分别为0.92±0.61和1.70±0.02。屈光状态：123例RP患者有不同程度的近视,占患者总数的89.8％。OCT检查提示黄斑区神经上皮层变薄,ADRP患者≥51岁组平均黄斑中心凹厚度为（185.73±1.23）μm;ARRP及XLRP患者21～30岁组,平均黄斑中心凹厚度为(173.21±0.98)、(170.49±1.15) μm。结论 ADRP、XLRP表现为典型RP,非典型RP均为ARRP或散发型RP。非典型RP中以无色素型RP多见,在儿童期易误诊为弱视。ARRP及XLRP较早累及黄斑区光感受器,21～30岁时即可出现明显的中心视力损害;ADRP较晚出现中心视力损害,51岁后仍能保持一定的中心视力。     

Prevalence of retinitis pigmentosa in Maine

Between 1976 and 1980, medical and social service sources were used to ascertain cases of retinitis pigmentosa in Maine (1980 population, I, 124,660). As of July 1, 1980, 241 clinically prevalent cases of retinitis pigmentosa were ascertained. Extensive pedigrees were collected for 185 of the subjects and medical records were obtained. One hundred fourteen cases were further evaluated by clinical examination including electroretinography. Adjusting for incorrect diagnosis (eight of 114, 7%) and underascertainment (23 of 185, 12.5%), we estimated that prevalence of retinitis pigmentosa in Maine is 236 cases, 21 per 100,000 population or 1:4,756. Excluding Usher and Bardet-Biedl syndromes, the prevalence is 1:5,193. Estimated birth incidence of persons who will become affected with non-syndrome retinitis pigmentosa is 1:3,544. Incidence of newly diagnosed cases per year is about six per 1,000,000 population. Among kindreds, 16 of 85 (19%) were autosomal dominant, 55 of 85 (65%) autosomal recessive or isolated cases, seven of 85 (8%) X-linked recessive, and seven of 85 (8%) not classified by mode of transmission.     

A genetic analysis of retinitis pigmentosa.

Genetic analysis of 457 patients with retinitis pigmentosa (RP) included categorisation of families by recognised mendelian pattern of inheritance and formal segregation analysis of all informative sibships. Of the 368 probands a surprisingly high 18% (68) had significant congenital loss of hearing and were diagnosed as having Usher syndrome. The RP probands were categorised as: 21.7% autosomal dominant, 9.0% X-linked, 16.0% autosomal recessive, 3.3% genetic type uncertain, and 50.0% simplex. Segregation analysis reflected this high proportion of simplex cases, accounting for reduced penetrance in dominant families; only 20% remain classified as sporadic (possibly nongenetic). In the matings between normal persons estimates of the segregation ratio also indicate lower values than expected. Unlike in RP sibship, segregation in the Usher syndrome is consistent with the hypothesis of recessive inheritance. Therefore RP with significant hearing loss segregates as expected, while even if a proband is classified as a dominant or recessive the recurrence risk for the RP phenotype may be below mendelian expectation.     

Preserved para-arteriole retinal pigment epithelium (PPRPE) in retinitis pigmentosa.

Five patients with retinitis pigmentosa (RP) with probable autosomal recessive inheritance have been identified in whom there is relative preservation of retinal pigment epithelium adjacent to and under retinal arterioles despite a panretinal degenerative process. All the patients were hypermetropic, though patients with RP tend to be myopic. This implies that there is a factor associated with retinal arterioles which locally retards the RP process in these patients. It may be appropriate to look for the PPRPE pattern in hypermetropic RP patients.     

Studies on retinitis pigmentosa in man. II. Erythrocyte osmotic fragility.

The osmotic fragility of erythrocytes from patients with genetically classified forms of retinitis pigmentosa (RP) has been studied. The mean fragility was increased in autosomal dominantly inherited RP, where the dystrophy was expressed regionally in the retina, with both rods and cones affected. In contrast it was normal in patients with the dominantly inherited disease, which leads to a diffusely distributed dystrophy of, predominantly, rod photoreceptor cells. Raised osmotic fragility of erythrocytes has also been observed in female patients with multiplex (recessive) RP and in female carriers of the X-linked form of the disease.     

The incidence of HLA-SD antigens in recessive retinitis pigmentosa.

Eighteen patients with recessive retinitis pigmentosa were tissue typed for HLA-SD antigens. There was no evidence that a particular HLA-SD antigen was associated with autosomal recessive retinitis pigmentosa.