A novel complex mutation event in the peripherin/RDS gene in a family with retinal pattern dystrophy

PURPOSE: To report a complex mutation in the peripherin/RDS gene found in a family in whom retinal pattern dystrophy is segregating as an autosomal dominant trait. METHODS: Clinical data were collected from family members of a large Swiss family affected by autosomal dominant retinal pattern dystrophy. Single strand conformation polymorphism (SSCP) analysis of the candidate gene peripherin/RDS and subsequent sequencing of the first exon were performed. RESULTS: Pattern dystrophy of the retina was suspected in 18 family members aged 30 years or older. Assuming a homogeneous phenotype, the candidate locus peripherin/RDS was investigated. SSCP analysis of the first exon of the peripherin/RDS gene showed an aberrant pattern in 18 affected individuals. Direct sequencing of polymerase chain reaction products detected a complex mutation, del265-268GCCA ins AGGGCC, leading to a stop codon at amino acid position 99. CONCLUSION: To our knowledge, we report the first complex mutation in the peripherin/RDS gene as the cause of a mild macular phenotype, supporting the importance of molecular diagnosis in genetic counseling.     

The contrast sensitivity of the squirrel monkey (Saimiri sciureus)

The contrast sensitivity of three squirrel monkeys and two human subjects was measured under similar conditions with a modified method of constant stimuli. Sensitivity was greatest for all subjects at 2–5c/deg and declined at higher and lower spatial frequencies. The high frequency limit of resolution was approx 35 c/deg for two monkeys and the human subjects and 17 c/deg for the other monkey. These results agree closely with previous visual acuity measurements for both species when luminance differences are taken into account. At the low photopic luminance used in the present study, the spatial vision of humans and squirrel monkeys appears very similar.     

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.     

Splice site mutation in the peripherin/RDS gene associated with pattern dystrophy of the retina.

PURPOSE: To report the phenotype and genotype of a splice site mutation at intron 2 of the peripherin/RDS gene in four half-siblings with pattern dystrophy of the retina. DESIGN: Experimental study. METHODS: In four siblings with a common mother and three separate fathers, complete ophthalmic examination, pedigree, electrophysiologic testing, and fluorescein angiography studies were obtained. Genomic DNA from serum lymphocytes was isolated and used as a template for primers specific for the cone homeobox gene (CRX), rhodopsin (RHO), and peripherin/RDS genes to conduct single stranded conformational analysis and cycle sequencing. RESULTS: The pedigree of four affected siblings suggested probable autosomal dominance transmission of pattern dystrophy. In the four siblings, best corrected visual acuity ranged from 20/20 to 20/80 by Snellen chart. Clinical findings included discrete, localized degenerative changes of the macular retinal pigment epithelium in all patients, with subclassification foveal. One patient exhibited pigment clumping within the atrophic areas. Another patient exhibited yellow flecks diffusely in the macula. Fluorescein angiographic findings included central hypofluorescence with a surrounding rim of hyperfluorescence that corresponded to the observed fundus lesions and window defects. There was a range of electroretinography (ERG) and electrooculography (EOG) findings. One patient demonstrated both cone and rod dysfunction on ERG testing and another demonstrated decreased rod function. EOG testing was normal in two patients and mildly diminished in one patient. DNA sequencing identified a point mutation in intron 2 of the peripherin/RDS gene, consisting of an A to T change at 1068+3, present in all four affected patients. CONCLUSIONS : Four siblings with pattern dystrophy of the retina presented a splice site mutation in the peripherin/RDS gene.     

Evaluation of the peripherin/RDS gene as a candidate gene in families with age-related macular degeneration

Age-related macular degeneration (AMD) is a heterogeneous group of disorders and is the leading cause of blindness in the elderly. While degeneration changes in the macula can occur at any time in life, it is the most common cause of severe visual impairment with advancing age. The disease affects approximately 11 million Americans and causes loss of central vision, impairing activities such as reading. The exact cause of the disorder is not known. In this report, we studied two unrelated families having familial-type AMD, with the assumption that mutations in the peripherin/retinal degeneration slow (RDS) gene could contribute to the disease phenotype. Our extensive analyses have identified two silent mutations (84D and 106V) in one family in the same allele of exon 1 which segregated in 3 patients with AMD. However, the fourth affected individual in the same family, as well as 40 normal controls, did not contain this mutation. Further analysis of exon 2 and exon 3 in both families did not show any other sequence alterations. Since one of these silent mutations (106V) has been reported to exist in certain general populations and the other mutation (84D) failed to segregate completely in the family, it is unlikely that these mutations are pathogenic. The results of the study suggest that the peripherin/RDS gene is not a major factor responsible for AMD in the families analyzed.     

Peripherin/RDS gene mutation (Pro210Leu) and polymorphisms in Japanese patients with retinal dystrophies

PURPOSE: To determine the frequency of peripherin/RDS (retinal degeneration slow) gene mutations in Japanese patients with retinal dystrophies. METHODS: We analyzed the peripherin/RDS gene in 54 unrelated Japanese patients with retinal dystrophies. Genomic DNA was amplified by polymerase chain reaction (PCR) and the PCR products were sequenced. We also examined 100 healthy subjects, seeking mutations or variations of the peripherin/RDS gene. RESULTS: Of the 54 Japanese patients, one with retinitis pigmentosa had a heterozygous C to T change at the second nucleotide at codon 210 of exon 2 (CCT to CTT/Pro210Leu) of the peripherin/RDS gene. None of the 100 individuals with normal fundi had the Pro210Leu mutation of the peripherin/RDS gene. Three variants of the peripherin/RDS gene (GTC to GTT/Val106Val, Glu304Gln, and Gly338Asp) were also found. The first variation (GTC to GTT/Val106Val) was silent. Two concurrent missense variations (Glu304Gln and Gly338Asp) were seen in 25.9% of the affected patients and in 29% of the healthy individuals. CONCLUSION: A novel mutation (Pro210Leu) of the peripherin/RDS gene has been found in one Japanese patient with retinitis pigmentosa. The alterations of Val106Val, Glu304Gln, and Gly338Asp may be polymorphic variants in the Japanese population.     

Macular appearance by means of OCT and electrophysiology in members of two families with different mutations in RDS (the peripherin/RDS gene)

PURPOSE: To describe the phenotype using electroretinography and optical coherence tomography (OCT) in members of two families with different mutations in RDS. METHODS: DNA was extracted from blood samples and used for mutation screening by denaturing gradient gel electrophoresis (DGGE) and nucleotide sequencing of RDS exons. Patients were examined with clinical evaluation, full-field electroretinography (ERG), multifocal electroretinography (mfERG) and OCT. RESULTS: An Arg-46 --> stop codon conversion and a Ser-125 --> Leu substitution were found, respectively, in affected members of the two families. Phenotypes included retinitis pigmentosa, central areolar choroidal dystrophy, macular dystrophy and adult vitelliform maculopathy. The vitelliform lesion was clearly delineated on OCT, but mfERG showed preserved function. Optical coherence tomography showed attenuation of retinal reflectivity in two cases. CONCLUSION: By combining traditional investigations with mfERG and OCT, we were able to obtain a more refined evaluation of contributing macular and generalized retinal dysfunction, respectively, in patients with hereditary retinal disease.     

Lactate dehydrogenase (LDH) isoenzymes in the retina of the sheep and changes associated with progressive retinal degeneration (Bright Blindness)

Total LDH activity and iosenzyme patterns have been determined in the retinal tissues of sheep. Changes occurring during normal development were studied in lambs and adult Clun × ewes. Total activity increased only slightly with age but there were pronounced changes in the LDH isoenzyme pattern. Redistribution of activity was associated with an increase in the ratio of H-type to M-type monomer (1·39 to 2·31). Slight but significant breed differences were observed when the retinas of Clun × ewes were compared with Swaledale adults. Total LDH activity (per g fresh weight or per mg protein) was less in the retinas of blind Swaledale ewes than in control tissues from normal (sighted) adults. Alterations in the isoenzyme pattern appeared to be an extension of the changes seen in normal development and was characterized by an increased ratio of H-type to M-type monomer (mean value 3·48). The enzyme changes observed in the retinal dystrophy of Bright Blindness were similar to those occurring in “retinitis pigmentosa” and in sodium iodate poisoning.     

Later retinal degeneration following childhood surgical aphakia in a family with recessive CRYAB mutation (p.R56W)

Purpose:?To describe later retinal degeneration following childhood cataract surgery without intraocular lens implantation in a consanguineous family with developmental cataract from homozygous p.R56W mutation in CRYAB, a gene that encodes a heat-shock protein (αB-crystallin) in both retina and the lens.

Methods:?Prospective ophthalmologic examination and venous blood sampling for diagnostic CRYAB sequencing in the 12 available family members (7 siblings and their 2 parents, the siblings’ maternal aunt and her son, and the siblings’ maternal grandmother).

Results:?Those who underwent childhood cataract surgery (2 siblings, their mother, their maternal aunt) or who had visually-insignificant lens opacities (2 siblings, their maternal grandmother) were homozygous for p.R56W CRYAB mutation. Among these 7 affected family members, clinically-obvious rod-cone degeneration was present only in the only 2 adults who were aphakic since childhood from cataract surgery.

Conclusions:?Recessive p.R56W CRYAB mutation shows variable expressivity for lens opacity. Decades of aphakia increases retinal light exposure and may be an environmental risk factor for significant retinal degeneration in patients homozygous for the mutation.     

A novel p.R890C mutation in EPHA2 gene associated with progressive childhood posterior cataract in a Chinese family

AIM:To identify the genetic defect in a Chinese family with bilateral progressive childhood posterior cataract.METHODS: A two-generation family was recruited in this study. Family history and clinical data were recorded. All reported candidate genes associated with congenital posterior cataract were screened by direct DNA sequencing.RESULTS: All affected individuals presented posterior opacities in the lens. Direct sequencing of the candidate genes showed a heterozygous c. 2668C>T variation in EPHA2 gene, which resulted in the replacement of arginine by cysteine at codon 890 (p. R890C). This mutation was found in two affected individuals, but was not observed in 200 normal controls.CONCLUSION: We report a novel mutation (p. R890C) in the EPHA2 receptor tyrosine kinase gene. The finding expands the mutation spectrum of EPHA2 in association with posterior cataract.     

Phenotype associated with an R120X nonsense mutation in the RP2 gene in a Japanese family with X-linked retinitis pigmentosa

We examined a Japanese family with X-linked retinitis pigmentosa (RP) associated with a nonsense mutation, R120X, in the RP2 gene. The 26-year-old proband presented at the age of seven years with a two-year history of night blindness. Visual disability worsened with increasing age. At age 24, visual acuity was 0.08 in both eyes. Testing for refractive error indicated mild myopia. Visual fields showed bilateral-constriction to 10 degrees. He had central macular areolar sclerosis in both eyes. Two maternal uncles had vision of light perception to hand movement in their early forties together with dense bilateral cataracts. The ocular phenotype of this family with R120X was considered severe; reported phenotypes associated with this mutation have not been uniform.     

A novel splice site mutation of CRYBA3/A1 gene associated with congenital cataract in a Chinese family

AIM: To identify the disease-causing mutation responsible for the presence of congenital cataract in a Chinese family. METHODS: The study recruited a four-generation Chinese pedigree affected by autosomal dominant congenital cataract (ADCC). Family history and the history of cataract extraction were recorded. Blood samples were collected from individuals for DNA extraction. Direct sequencing of congenital cataract-associated genes was performed. Single-strand conformational polymorphism and bioinformatic analysis were conducted to further study the mutation. RESULTS: Direct sequencing revealed a novel splice site mutation of c.30-2 A>G in the CRYBA3/A1 gene. The mutation co-segregated within all affected individuals in the family and was not found in unaffected members or 100 unrelated normal controls. These results were further confirmed by single-strand conformational polymorphism and bioinformatic analysis using the Human Splicing Finder and MaxEnt online software and Annovar computer software. CONCLUSION: c.30-2 A>G mutation of CRYBA3/A1 gene is a novel mutation and broadens the genetic spectrum of ADCC.