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.     

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。     

On variants and disease-causing mutations: Case studies of a SEMA4A variant identified in inherited blindness

The p.R713Q variant of the semaphorin‐4a‐encoding gene, SEMA4a, has been reported to cause autosomal dominant retinitis pigmentosa. Here we show three families with retinal degeneration in which unaffected family members are either homozygous or heterozygous for the variant. The p.R713Q variant in SEMA4A is insufficient to cause either autosomal recessive or autosomal dominant retinitis pigmentosa and is unlikely to be pathogenic.     

Early-Onset X-Linked Retinitis Pigmentosa in a Heterozygous Female Harboring an Intronic Donor Splice Site Mutation in the Retinitis Pigmentosa GTPase Regulator Gene

Purpose: To report a heterozygous female presenting with an early-onset and severe form of X-linked retinitis pigmentosa (XLRP).

Patients and Methods: This is a case series presenting the clinical findings in a heterozygous female with XLRP and two of her family members. Fundus photography, fundus autofluorescence, ocular coherence tomography, and visual perimetry are presented.

Results: The proband reported here is a heterozygous female who presented at the age of 8 years with an early onset and aggressive form of XLRP. The patient belongs to a four-generation family with a total of three affected females and four affected males. The patient was initially diagnosed with retinitis pigmentosa (RP) at the age of 4 years. Genetic testing identified a heterozygous donor splice site mutation in intron 1 (IVS1?+?1G?>?A) of the retinitis pigmentosa GTPase regulator gene. The father of the proband was diagnosed with RP when he was a young child. The sister of the proband, evaluated at the age of 6 years, showed macular pigmentary changes.

Conclusions: Although carriers of XLRP are usually asymptomatic or have a mild disease of late onset, the proband presented here exhibited an early-onset, aggressive form of the disease. It is not clear why some carrier females manifest a severe phenotype. A better understanding of the genetic processes involved in the penetrance and expressivity of XLRP in heterozygous females could assist in providing the appropriate counseling to affected families.     

Genetic analysis of Chinese families reveals a novel truncation allele of the retinitis pigmentosa GTPase regulator gene

AIM: To make comprehensive molecular diagnosis for retinitis pigmentosa (RP) patients in a consanguineous Han Chinese family using next generation sequencing based Capture-NGS screen technology. METHODS: A five-generation Han Chinese family diagnosed as non-syndromic X-linked recessive RP (XLRP) was recruited, including four affected males, four obligate female carriers and eleven unaffected family members. Capture-NGS was performed using a custom designed capture panel covers 163 known retinal disease genes including 47 RP genes, followed by the validation of detected mutation using Sanger sequencing in all recruited family members. RESULTS: Capture-NGS in one affected 47-year-old male reveals a novel mutation, c.2417_2418insG:p.E806fs, in exon ORF15 of RP GTPase regulator (RPGR) gene results in a frameshift change that results in a premature stop codon and a truncated protein product. The mutation was further validated in three of four affected males and two of four female carriers but not in the other unaffected family members. CONCLUSION: We have identified a novel mutation, c.2417_2418insG:p.E806fs, in a Han Chinese family with XLRP. Our findings expand the mutation spectrum of RPGR and the phenotypic spectrum of XLRP in Han Chinese families, and confirms Capture-NGS could be an effective and economic approach for the comprehensive molecular diagnosis of RP.     

一白族视网膜色素变性家系致病基因筛查

目的探讨一白族常染色体显性遗传视网膜色素变性（adRP）家系致病基因与PRPF31、IMPDH、RDS基因多发突变位点的关系。方法采集一连续5代发病的白族adRP家系静脉血3～5mL，提取基因组DNA。应用聚合酶链反应（PCR）对常见的3个adRP候选基因（PRPF31、IMPDH1、RDS）的多发突变位点进行扩增，PCR产物纯化后直接测序；测序结果与GenBank数据库中核酸序列进行Blast分析。结果该白族家系22例成员中，11例（50％）存在PRPF31基因第6内含子4个碱基的缺失（IVS6—78_IVS6—75del4CACA，rs57960425），其中包括7例（53．8％）adRP患者和4例（44．4％）正常个体；11例（50％）存在IVS6—31C／T（rs2303557）变异，包括8例（61．5％）adRP患者和3例（33．3％）正常个体。IMPDH1基因和RDS基因的多发突变位点在该白族家系中未发现任何变异。结论rs57960425及rs2303557为PRPF31基因中的单核苷酸多态，与该家系的发病无直接相关，该家系的致病基因可能与其他基因有关。     

Autosomal recessive retinitis pigmentosa is associated with mutations in RP1 in three consanguineous Pakistani families

PURPOSE: To localize and identify the gene and mutations causing autosomal recessive retinitis pigmentosa in three consanguineous Pakistani families. METHODS: Blood samples were collected and DNA was extracted. A genome-wide scan was performed by using 382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and lod scores were calculated. RESULTS: A genome-wide scan of 25 families gave an hlod = 4.53 with D8S260. Retinitis pigmentosa in all three families mapped to a 14.21-cM (21.19-Mb) region on chromosome 8 at q11, flanked by D8S532 and D8S260. This region harbors RP1, which is known to cause autosomal dominant retinitis pigmentosa. Sequencing of the coding exons of RP1 showed mutations in all three families: two single-base deletions, c.4703delA and c.5400delA, resulting in a frame shift, and a 4-bp insertion, c.1606insTGAA, all causing premature termination of the protein. All affected individuals in these families are homozygous for the mutations. Parents and siblings heterozygous for the mutant allele did not show any signs or symptoms of RP. CONCLUSIONS: These results provide strong evidence that mutations in RP1 can result in recessive as well as dominant retinitis pigmentosa. The findings suggest that truncation of RP1 before the BIF motif or within the terminal portion results in a simple loss of RP1 function, producing a recessive inheritance pattern. In contrast, disruption of RP1 within or immediately after the BIF domain may result in a protein with a deleterious effect and hence a dominant inheritance pattern.     

视网膜色素变性患者视紫红质E341ter基因突变及临床表型分析

目的 探讨常染色体显性遗传视网膜色素变性患者视紫红质基因突变及其与临床表型的关系。方法 应用聚合酶链反应（polymerase chain reaction,PCR)和单链构象多态性（single strand conformation polymorphism,SSCP)技术,对13个常染色体显性遗传视网膜色素变性家系的27例成员,进行视紫红质基因整个编码区的突变筛选,对SSCP检测有变异带的外显子PCR产物进行测序;同时应用裂隙灯、眼底镜、动静态视地和视网膜电流图（ERG）对患者进行临床检测。随机收集30例正常人进行对照检测。结果 发现1个家系患者有视紫红质E341ter突变,呈杂合子,密码子341第一个碱基由G变成T。该家系临床表现为青年期出现夜盲,视力和视野损害较重,ERG检查杆体和锥体无反应或仅有较小的锥体反应。结论 视紫红质基因突变家系的视网膜色素变性病史开始于杆体功能的丢失,进而累及锥体系统,并最终导致视功能严重丧失。视紫红质E341ter突变被认为是该家系的病因。     

Clinical and serum lipid findings in a large family with autosomal dominant retinitis pigmentosa

Retinitis pigmentosa, of unknown cause, has recently been associated with decreased amounts of the polyunsaturated fatty acid, docosahexaenoic acid, in the plasma of affected as compared with unaffected relatives. It has been suggested that this finding may serve as a marker for the disease and might indicate alterations in photoreceptor cell metabolism. The authors studied 54 members of a family with dominantly inherited retinitis pigmentosa in five generations. In addition to the typical clinical findings of retinitis pigmentosa, eight persons also had a bull's eye maculopathy, and four persons had uni- or bilateral optic nerve drusen. When the authors determined the plasma fatty acid and lipid contents, they saw the expected age-related effect on cholesterol and triglycerides, but an unexpected, significant reduction in fatty acids in the unaffected controls as compared with persons with retinitis pigmentosa. The authors' results emphasize the heterogeneity of phenotypic expression of retinitis pigmentosa within a single family.     

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PRPF-31基因剪接位点突变及其相关表型特征研究

目的 研究一个常染色体显性遗传视网膜色素变性（ADRP）大家系的致病基因及其相关表型特征。方法 应用基因组扫描定位和突变检测法确定该家系的致病基因,并对其进行详细的家系调查,同时选取该家系不同代别中11例有症状的患者和7例无症状的个体,进行视网膜电图（ERG）、多焦视网膜电图（mERG）、心理物理学及荧光素眼底血管造影等检测。结果 在19号染色体PRPF-31基因5号内含子-1处发现一新的剪接位点突变（IVS5—1G→A）。家系中有症状的患者均在10岁以前发病,病情进展快而严重,呈Ⅰ型弥漫性视网膜色素变性（RP）表现。Goldmann视野检查,30岁以上患者动态视野大范围缺损,部分患者仅存颞侧视岛,静态视野阈值无法查出;mERG检测：双眼暗视a、b波振幅极度下降且低平,呈熄灭型;多焦视网膜电图显示双眼黄斑区及其周围视网膜反应密度显著降低;荧光素眼底血管造影显示黄斑中央凹周围色素上皮萎缩,呈“牛眼样”外观。7例无症状者中,1例经mERG、心理物理学及分子遗传学检测,证实其为轻症RP患者,另1例为疾病基因的杂合携带者。结论 PRPF-31基因5号内含子-1剪接位点突变（IVS5—1G→A）是ADRP的一种新的突变位点。该突变所致的ADRP表型主要为Ⅰ型弥漫性RP,同时,还存在基因外显不全和表现度不一的变异性表达。     

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.     

Rhodopsin gene codon 106 mutation (Gly-to-Arg) in a Japanese family with autosomal dominant retinitis pigmentosa

PURPOSE: To examine rhodopsin gene mutations in Japanese patients with retinitis pigmentosa. METHODS: We performed a mutational analysis of the rhodopsin gene in 42 patients from 40 families with retinitis pigmentosa. Genomic DNA was amplified by polymerase chain reaction (PCR) and the PCR products were sequenced. Restriction enzyme analysis was performed in family members of 1 patient with a rhodopsin gene mutation (Gly106Arg) and in 100 normal individuals. RESULTS: Among the patients with retinitis pigmentosa, 3 patients in one family had a heterozygous Gly106Arg mutation of the rhodopsin gene. They had night blindness and sectorial retinal dystrophy (predominantly at the inferior fundus) in both eyes. None of the 100 individuals with normal fundi had the Gly106Arg mutation of the rhodopsin gene. CONCLUSION: The Gly106Arg mutation of the rhodopsin gene has been found in Japanese patients with sectorial retinitis pigmentosa.     

Attitudes regarding predictive testing for retinitis pigmentosa

PURPOSE: To assess attitudes towards predictive testing for autosomal dominant retinitis pigmentosa (ADRP). METHODS: A prospective questionnaire study of 46 affected adults and their adult family members identified from pedigrees clearly consistent with ADRP or who had had DNA-testing confirmation of ADRP before the study commenced. RESULTS: High proportions of unaffected siblings (73%) and patients (67%) agreed to prenatal testing. Patients agreed to prenatal testing. Patients agreed significantly more often than unaffected siblings that treatment should be available prior to initiating predictive testing. Psychoemotional distress was reported in 57% of the affected adults and their family members in recollecting their own predictive testing as children. CONCLUSIONS: ADRP families indicate a favorable attitude towards testing presymptomatic children with counseling to lessen the psychological and social impact of results.     

常染色体显性视网膜色素变性家系的基因连锁定位和候选基因的序列分析

目的对一常染色体显性视网膜色素变性（RP）家系进行致病基因的连锁定位，并对候选基因进行序列分析。方法在家系中进行全基因组扫描以确定与疾病连锁的染色体区域，对该区域附近的候选基因进行直接序列分析。结果此家系致病基因的最小可能区域（MCR）被定位于19号染色体微卫星标记D19S246和D19S601之间不到5厘摩（cM）的区域。对该区域附近的候选基因进行直接序列分析的结果并未发现致病性基因突变。结论CRX（锥杆细胞同源基因）和PRPF3l基因是该家系的非致病性基因，在19号染色体上可能存在导致常染色体显性视网膜色素变性（adRP）的新的致病基因。     

Nettleship's two pedigrees of retinitis pigmentosa: a historical postscript

Two pedigrees of retinitis pigmentosa, originally published by Nettleship, are presented with extracts from his private correspondence. Affected descendants from the two families have been traced, in one family extending the pedigree to nine affected generations, and in the other providing an instance of male-to-male transmission in a pedigree previously considered as being possibly X-linked.     

常染色体显性视网膜色素变性家系视紫红质基因突变的检测分析

目的 观察一个常染色体显性视网膜色素变性(autosomal dominant retinitis pigmentosa,ADRP)家系的视紫红质(rhodopsin,RHO)基因突变特征。 方法 抽取20个ADRP家系成员外周血3～5 ml并提取DNA；聚合酶链反应(polymerase chain reaction,PCR)扩增RHO基因第1～5外显子基因片段, 用直接测序法对20个DNA样本进行RHO基因突变检测。 结果 该家系中10例ADRP患者的RHO基因的第182密码子发生G→A置换突变(Gly-182-Asp)，而在2例患者和8个未患病家系成员中均未发现此突变。 结论 Gly-182-Asp突变不一定是ADRP家系的致病原因;在RHO基因附近可能存在新的基因, 但还需要进一步研究证明。 (中华眼底病杂志, 2002, 18: 256-258)     

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.     

Associated retinitis pigmentosa and fundus flavimaculatus

A family is described with 2 members, father and son, affected by associated retinitis pigmentosa and fundus flavimaculatus, whereas 1 other member had a combination of retinitis pigmentosa and unilateral central areolar atrophy, 1 member a fundus flavimaculatus with electroretinographic findings indicative of a subclinical form of retinitis pigmentosa and the last one with electroretinographic findings indicative of a subclinical form of retinitis pigmentosa.