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.     

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.     

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.     

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.     

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.     

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.     

Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus

AIM: To describe the phenotype and to analyse the peripherin/RDS gene in 10 unrelated families with multifocal pattern dystrophy simulating Stargardt disease (STGD1). METHODS: The probands of 10 families and 20 affected family members underwent an ophthalmic examination including dilated fundus examination, fundus autofluorescence imaging and optical coherence tomography (OCT). In all probands and in selected family members, fluorescein angiography, electrophysiological testing and visual field analysis were performed. Blood samples were obtained from affected and unaffected family members for analysis of the peripherin/RDS gene. RESULTS: All 10 probands carried mutations in the peripherin/RDS gene. Nine different mutations were identified, including six mutations that were not described previously. All probands showed a pattern dystrophy with yellow-white flecks in the posterior pole that strongly resembled the flecks seen in STGD1, on ophthalmoscopy as well as on autofluorescence and OCT. Clinical findings in the family members carrying the same mutation as the proband were highly variable, ranging from no visible abnormalities to retinitis pigmentosa. CONCLUSIONS: Mutations in the peripherin/RDS gene are the major cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. This autosomal dominant disorder should be distinguished from autosomal recessive STGD1, in view of the different inheritance pattern and the overall better visual prognosis.     

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。     

Absence of abnormal erythrocyte superoxide dismutase, copper, or zinc levels in patients with retinitis pigmentosa.

Blood samples obtained from 22 patients with retinitis pigmentosa, 6 unaffected family members, and 8 unrelated controls showed serum copper and zinc to be in the normal range, contrary to the results in earlier reports. Likewise no significant variation of erythrocyte superoxide dismutase (SOD) and catalase levels was found between the 3 groups or when the patients were grouped by sex, age, or genetic distribution. The SOD proteins from controls and retinitis pigmentosa patients had identical mobilities on gel electrophoresis, isoelectric points, and heat stabilities. Our studies do not support the use of copper, zinc, or SOD in the diagnosis or treatment of retinitis pigmentosa.     

Phenotypic expression of autosomal dominant retinitis pigmentosa in a Swedish family expressing a Phe-211-Leu variant of peripherin/RDS

PURPOSE : To characterize the clinical phenotype, with emphasis on electrophysiology, of members of a Swedish family with autosomal dominant retinitis pigmentosa due to a novel mutation, F211L, in the peripherin/RDS gene. METHODS : Nine patients with autosomal dominant retinitis pigmentosa and two healthy family members underwent a full clinical evaluation including kinetic visual field testing, measurement of dark adaptation threshold, and full-field electroretinography. Blood samples were collected and DNA analysis was performed using denaturing gradient gel electrophoresis (DGGE). RESULTS : The grandfather, six of seven siblings from the middle generation, and two young boys carried the mutation F211L in the peripherin/RDS gene. The mutation segregated with the clinical presentation of disease. Fundus examination revealed mainly macular atrophy. All assessed parameters of retinal function (visual acuity, dark adaptation threshold, visual fields, and full-field electroretinograms) demonstrated a successive reduction with increasing age. Full-field electroretinograms showed a diminished rod response in all affected individuals and a reduction of the cone b-wave amplitudes with increasing age, indicating retinitis pigmentosa. In the affected family members, the disease seems to progress at a similar rate with increasing age. CONCLUSIONS : The peripherin/RDS gene mutation F211L is associated with a clinical phenotype and includes early loss of rod function and successive reduction of cone function with increasing age, but impressively well-preserved visual acuity and visual fields in young and middle-aged patients and moderately reduced vision in the old patient. Compared to previously described phenotypes segregating with mutations in the peripherin/RDS gene, the present family demonstrates a more benign clinical phenotype, which is concordant within the family.     

Early-onset autosomal dominant retinitis pigmentosa with severe hyperopia

We studied a four-generation family with early-onset autosomal dominant retinitis pigmentosa, severe hyperopia, and axial eye lengths of less than 20 mm. The affected members had decreased vision, night blindness, typical peripheral retinal pigmentary changes, and electroretinographic abnormalities characteristic of retinitis pigmentosa. This pedigree suggests there is another variant of retinitis pigmentosa associated with hyperopia besides Leber's congenital amaurosis and preserved para-arteriole retinal pigment epithelium.     

Concentric retinitis pigmentosa: clinicopathologic correlations

Progressive concentric (centripetal) loss of vision is one pattern of visual field loss in retinitis pigmentosa. This study provides the first clinicopathologic correlations for this form of retinitis pigmentosa. A family with autosomal dominant concentric retinitis pigmentosa was examined clinically and with visual function tests. A post-mortem eye of an affected 94 year old family member was processed for histopathology and immunocytochemistry with retinal cell specific antibodies. Unrelated simplex/multiplex patients with concentric retinitis pigmentosa were also examined. Affected family members of the eye donor and patients from the other families had prominent peripheral pigmentary retinopathy with more normal appearing central retina, good visual acuity, concentric field loss, normal or near normal rod and cone sensitivity within the preserved visual field, and reduced rod and cone electroretinograms. The eye donor, at age 90, had good acuity and function in a central island. Grossly, the central region of the donor retina appeared thinned but otherwise normal, while the far periphery contained heavy bone spicule pigment. Microscopically the central retina showed photoreceptor outer segment shortening and some photoreceptor cell loss. The mid periphery had a sharp line of demarcation where more central photoreceptors were near normal except for very short outer segments and peripheral photoreceptors were absent. Rods and cones showed abrupt loss of outer segments and cell death at this interface. It is concluded that concentric retinitis pigmentosa is a rare but recognizable phenotype with slowly progressive photoreceptor death from the far periphery toward the central retina. The disease is retina-wide but shows regional variation in severity of degeneration; photoreceptor death is severe in the peripheral retina with an abrupt edge between viable and degenerate photoreceptors. Peripheral to central gradients of unknown retinal molecule(s) may be defective or modify photoreceptor degeneration in concentric retinitis pigmentosa.     

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 dominant cataract: intrafamilial phenotypic variability, interocular asymmetry, and variable progression in four Chilean families

PURPOSE: To document intrafamilial and interocular phenotypic variability of autosomal dominant cataract (ADC). DESIGN: Prospective observational case series. METHODS: We performed ophthalmologic examination in four Chilean ADC families. RESULTS: The families exhibited variability with respect to morphology, location with the lens, color and density of cataracts among affected members. We documented asymmetry between eyes in the morphology, location within the lens, color and density of cataracts, and a variable rate of progression. CONCLUSIONS: The cataracts in these families exhibit wide intrafamilial and interocular phenotypic variability, supporting the premise that the mutated genes are expressed differentially in individuals and between eyes; other genes or environmental factors may be the bases for this variability. Marked progression among some family members underscores the variable clinical course of a common mutation within a family. Like retinitis pigmentosa, classification of ADC will be most useful if based on the gene and specific mutation.     

Vitamin A metabolism in primary retinitis pigmentosa

The serum vitamin A (VA) and retinol body pool response (RBPR) were studied in 28 cases of retinitis pigmentosa (RP), in comparison to 7 unaffected RP family members and 10 normal individuals. Serum VA was found to be normal in all 3 groups, with no significant difference between any 2 groups. The RBPR was also normal in all 3 groups, but the RBPR of the RP patients and their unaffected family members were significantly higher than the normal respectively (P less than 0.001), suggesting that the pigment epithelium or rod photoreceptor of the former groups were deficient in VA, whether from disturbed utilization or abnormalities in their retinol-binding protein, that abnormally high feedback stimuli were sent out calling for a VA supply to the target site with less retention in the liver.     

Copper metabolism in American retinitis pigmentosa patients.

Serum copper, serum caeruloplasmin, and urinary copper excretion were measured in 38 American patients (and 15 family members) with recessive, dominant, and X-linked forms of retinitis pigmentosa. No abnormalities were found, in contrast to the findings of a recent study on Indian patients. Our data argue against a role for copper metabolism in ordinary retinitis pigmentosa.     

Genetic study of retinitis pigmentosa in China

A total of 190 patients (379 eyes), from 169 families, with retinitis pigmentosa were studied in four genetic aspects in China. A large percentage (58.9%) of affected patients appear to be sporadic cases with no family history of disease. In dermatoglyphic analysis, comparing with the controls, the increment of eight or more whorls, the increase of the number of simian and the value of atd angle in 110 patients with retinitis pigmentosa were statistically significant. In addition, the incidence of G6PD deficiency in retinitis pigmentosa (7.89%) is higher than that (3.5%) of a nonaffected population in the same area. However, there is no significant difference of ABO blood typing between 176 patients with retinitis pigmentosa and the normal population of China.