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E L Berson

Publications and source records attributed to E L Berson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Mutations in a gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis pigmentosa.

The autosomal dominant retinitis pigmentosa (RP) locus, designated RP1, has been mapped through linkage studies to a 4-cM interval at 8q11-13. Here we describe a new photoreceptor-specific gene that maps in this interval and whose expression is modulated by retinal oxygen levels in vivo. This gene consists of at least 4 exons that encode a predicted protein of 2,156 amino acids. A nonsense mutation at codon 677 of this gene is present in approximately 3% of cases of dominant RP in North America. We also detected two deletion mutations that cause frameshifts and introduce premature termination codons in three other families with dominant RP. Our data suggest that mutations in this gene cause dominant RP, and that the encoded protein has an important but unknown role in photoreceptor biology.

Amino Acid Sequence↗
PubMed1999

Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus.

The metabolic pathways that produce 11-cis retinal are important for vision because this retinoid is the chromophore residing in rhodopsin and the cone opsins. The all-trans retinal that is generated after cone and rod photopigments absorb photons of light is recycled back to 11-cis retinal by the retinal pigment epithelium and Müller cells of the retina. Several of the enzymes involved have recently been purified and molecularly cloned; here we focus on 11-cis retinol dehydrogenase (encoded by the gene RDH5; chromosome 12q13-14; ref. 4), the first cloned enzyme in this pathway. This microsomal enzyme is abundant in the retinal pigment epithelium, where it has been proposed to catalyse the conversion of 11-cis retinol to 11-cis retinal. We evaluated patients with hereditary retinal diseases featuring subretinal spots (retinitis punctata albescens and fundus albipunctatus) and patients with typical dominant or recessive retinitis pigmentosa for mutations in RDH5. Mutations were found only in two unrelated patients, both with fundus albipunctatus; they segregated with disease in the respective families. Recombinant mutant 11-cis retinol dehydrogenases had reduced activity compared with recombinant enzyme with wild-type sequence. Our results suggest that mutant alleles in RDH5 are a cause of fundus albipunctatus, a rare form of stationary night blindness characterized by a delay in the regeneration of cone and rod photopigments.

Adaptation, Ocular↗
PubMed1999

Safety of <7500 RE (<25000 IU) vitamin A daily in adults with retinitis pigmentosa.

BACKGROUND: Vitamin A supplementation is being used successfully to treat some forms of cancer and the degenerative eye disease retinitis pigmentosa. The daily biological need for vitamin A is estimated to be 800 retinol equivalents (RE)/d (2667 IU/d) for adult women and 1000 RE/d (3300 IU/d) for adult men; doses > or = 7500 RE (> or = 25000 IU)/d are considered potentially toxic over the long term. OBJECTIVE: We assessed the safety in adults of long-term vitamin A supplementation with doses above the daily biological need but <7500 RE (<25000 IU)/d. DESIGN: Adults aged 18-54 y with retinitis pigmentosa but in generally good health (n = 146) were supplemented with 4500 RE (15000 IU) vitamin A/d for < or = 12 y (group A) and compared with a similar group (n = 149) that received 23 RE (75 IU)/d (trace group). Mean total consumption of vitamin A in group A was 5583 RE (18609 IU)/d (range: 4911-7296 RE/d, or 16369-24318 IU/d) and that in the trace group was 1053 RE (3511 IU)/d (range: 401-3192 RE/d, or 1338-10638 IU/d). RESULTS: Patients in group A showed an 8% increase in mean serum retinol concentration at 5 y and an 18% increase at 12 y (P < 0.001); no retinol value exceeded the upper normal limit (3.49 micromol/L, or 100 microg/dL). Mean serum retinyl esters were elevated approximately 1.7-fold at 5 y and remained relatively stable thereafter. No clinical symptoms or signs of liver toxicity attributable to vitamin A excess were detected. CONCLUSIONS: Prolonged daily consumption of <7500 RE (<25000 IU) vitamin A/d can be considered safe in this age group.

Adolescent↗
PubMed1999

Recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens.

PURPOSE: To determine the frequency and spectrum of mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein (CRALBP) in patients with hereditary retinal degeneration. METHODS: The single-strand conformation polymorphism (SSCP) technique and a direct genomic sequencing technique were used to screen the coding exons of this gene (exons 2-8) for mutations in 324 unrelated patients with recessive or isolate retinitis pigmentosa, retinitis punctata albescens, Leber congenital amaurosis, or a related disease. Variant DNA fragments revealed by SSCP analysis were subsequently sequenced. Selected alleles that altered the coding region or intron splice sites were evaluated further through segregation analysis in the families of the index cases. RESULTS: Four novel mutations were identified in this gene among three unrelated patients with recessively inherited retinitis punctata albescens. Two of the mutations were missense: one was a frameshift, and one affected a canonical splice donor site. CONCLUSIONS: Recessive mutations in the RLBP1 gene are an uncommon cause of retinal degeneration in humans. The phenotype produced by RLBP1 mutations seems to be a form of retinitis punctata albescens.

Adult↗
PubMed1999

Frequency of mutations in the gene encoding the alpha subunit of rod cGMP-phosphodiesterase in autosomal recessive retinitis pigmentosa.

PURPOSE: To determine the mutation spectrum of the PDE6A gene encoding the alpha subunit of rod cyclic guanosine monophosphate (cGMP)phosphodiesterase and the proportion of patients with recessive retinitis pigmentosa (RP) due to mutations in this gene. METHODS: The single-strand conformation polymorphism (SSCP) technique and a direct genomic sequencing technique were used to screen all 22 exons of this gene for mutations in 164 unrelated patients with recessive or isolate RP. Variant DNA fragments revealed by SSCP analysis were subsequently sequenced. Selected alleles that altered the coding region or intron splice sites were evaluated further through segregation analysis in the families of the index cases. RESULTS: Four new families were identified with five novel mutations in this gene that cosegregated with disease. Combining the data presented here with those published earlier by the authors, eight different mutations in six families have been discovered to be pathogenic. Two of the mutations are nonsense, five are missense, and one affects a canonical splice-donor site. CONCLUSIONS: The PDE6A gene appears to account for roughly 3% to 4% of families with recessive RP in North America. A compilation of the pathogenic mutations in PDE6A and those reported in the homologous gene PDE6B encoding the beta subunit of rod cGMP-phosphodiesterase shows that the cGMP-binding and catalytic domains are frequently affected.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1999

Acuity recovery and cone pigment regeneration after a bleach in patients with retinitis pigmentosa and rhodopsin mutations.

PURPOSE: To assess visual acuity recovery times and cone photopigment regeneration kinetics after a bleach in the fovea of patients with dominant retinitis pigmentosa due to rhodopsin mutations. METHODS: The authors measured acuity recovery times by computerized photostress testing in 13 patients with dominant retinitis pigmentosa and one of eight rhodopsin mutations. The authors also measured their time constants of cone photopigment regeneration with a video imaging fundus reflectometer to determine whether acuity recovery time depended on pigment regeneration kinetics. These values were compared with those of normal subjects, by the Mann-Whitney U test. The relationship between acuity recovery time and the time constant of cone photopigment regeneration among the patients was quantified by the Spearman rank correlation. RESULTS: The visual acuity recovery times, which averaged 22.0 seconds for the patients with retinitis pigmentosa and 11.2 seconds for the normal subjects, were significantly slower for the patient group (P < 0.001). The time constants of cone pigment regeneration, which averaged 172 seconds for the patients with retinitis pigmentosa and 118 seconds for the normal subjects, also were significantly slower for the patient group (P = 0.043). The authors also found a significant, positive correlation between the visual acuity recovery time and the time constant of pigment regeneration for the patients with retinitis pigmentosa (r = 0.65, P = 0.017). CONCLUSIONS: A slowing of foveal visual acuity recovery and cone pigment regeneration, which are related to each other, can occur in patients with retinitis pigmentosa, due to a rod-specific gene defect.

Adult↗
PubMed1998

Effect of vitamin A supplementation on rhodopsin mutants threonine-17 --> methionine and proline-347 --> serine in transgenic mice and in cell cultures.

A therapeutic effect of vitamin A supplementation on the course of photoreceptor degeneration, previously reported for patients with retinitis pigmentosa, was tested in two transgenic mouse models of this disease, each carrying a dominant rhodopsin mutation. The threonine-17 --> methionine (T17M) mutation is a class II rhodopsin mutation, characterized by a thermal instability/folding defect and minimal regeneration with the chromophore. The proline-347 --> serine (P347S) mutation belongs to class I, comprised of a smaller number of mutations that exhibit no recognized biochemical abnormality in vitro. In the present study, each of the two mouse models was fed a diet containing 2.5 mg of vitamin A palmitate (control) or 102.5 mg of vitamin A palmitate (high vitamin A) per kilogram of diet. Dark-adapted, full-field electroretinograms showed that the high vitamin A diet significantly reduced the rate of decline of a-wave and b-wave amplitudes in the T17M mice but had no significant effect on the decline of electroretinogram amplitude in the P347S mice. Correspondingly, histologic evaluation revealed that the treatment was associated with significantly longer photoreceptor inner and outer segments and a thicker outer nuclear layer in the T17M mice but had no effect on photoreceptor morphology in the P347S mice. In a separate series of experiments, the instability defect of the T17M mutant opsin expressed in vitro was partially alleviated by inclusion of 11-cis-retinal in the culture media. These results show that vitamin A supplementation slows the rate of photoreceptor degeneration caused by a class II rhodopsin mutation. Vitamin A supplementation may confer therapeutic benefit by stabilizing mutant opsins through increased availability of the chromophore.

Animals↗
PubMed1998

Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis.

RPE65 is a protein of unknown function expressed specifically by the retinal pigment epithelium. We examined all 14 exons of this gene in 147 unrelated patients with autosomal recessive retinitis pigmentosa (RP), in 15 patients with isolate RP, and in 45 patients with Leber congenital amaurosis (LCA). Sequence anomalies that were likely to be pathogenic were found in two patients with recessive RP, in one patient with isolate RP recategorized as recessive, and in seven patients with LCA. Cosegregation analysis in each available family showed that all affected individuals were either homozygotes or compound heterozygotes and that all unaffected individuals were either heterozygote carriers or homozygous wild type. In one family, there was one instance of a new mutation not present in either parent of the affected individual. In another family, affected members with recessive RP in three branches (i.e., three distinct pairs of parents) were compound heterozygotes for the same two mutations or homozygous for one of them. Based on our results, mutations in the RPE65 gene appear to account for approximately 2% of cases of recessive RP and approximately 16% of cases of LCA.

Blindness↗
PubMed1998

Histopathologic and immunohistochemical study of an autopsy eye with X-linked cone degeneration.

We performed a histopathologic and immunohistochemical study of eyes obtained at autopsy of an 84-year-old man from a family with X-linked cone degeneration in which affected members have a 6.5-kilobase deletion in the red cone pigment gene. At his most recent ocular examination, at age 71 years, this patient had had a visual acuity of 20/200 OU, fundus changes suggestive of macular degeneration, borderline-normal full-field rod electroretinograms, and profoundly reduced full-field cone electroretinograms. Histopathologic examination demonstrated marked loss of cone and rod photoreceptors and the retinal pigment epithelium in the central macula. The peripheral cone population was reduced, while the peripheral rod population was relatively preserved. Immunohistochemical examination with an antibody to both red and green cone opsin and an antibody to blue cone opsin disclosed a prominent loss of the red and green cone population and preservation of the blue cone population. These findings show that a defect in the red cone pigment gene can result in extensive degeneration of the red and green cone population across the retina.

Aged↗
PubMed1998

Rod and cone function in the Nougaret form of stationary night blindness.

BACKGROUND: Recently, a mutation (Gly38Asp) was identified in the alpha subunit of rod transducin in members of the Nougaret pedigree affected with dominantly inherited stationary night blindness. OBJECTIVE: To evaluate retinal function in patients with the Gly38Asp gene defect. DESIGN: Ocular examinations, including specialized measures of rod and cone function. SETTING: A clinical research facility in Boston, Mass. PATIENTS: A father (aged 48 years) and son (aged 25 years) with the Gly38Asp mutation. MAIN OUTCOME MEASURES: Psychophysical thresholds to white and narrowband lights and full-field electroretinographic (ERG) responses. RESULTS: Both patients showed dark-adapted thresholds to white light that were elevated approximately 2 log-units across the retina. Spectral sensitivity testing revealed thresholds that seemed to be governed mostly by rods. Although both patients' dark-adapted ERG responses to a dim blue flash were nondetectable, their dark-adapted ERGs to a white flash showed an a-wave with cone and rod components and a b-wave amplitude larger than what could have been generated by cone function alone. Rod ERGs to bright blue flashes had subnormal, but detectable, amplitudes that seemed to result from a profound reduction in sensitivity. The patients also showed loss of a cone subcomponent in the dark-adapted response to a red flash. The abnormal dark-adapted ERG responses of the patients could be simulated in the ERG responses of normal subjects tested with blue, white, and red flashes presented in the presence of a mesopic background. CONCLUSIONS: Although the Nougaret form of stationary night blindness has been cited as a prototype of absent rod function with normal cone function, our findings, based on the genealogically and genotypically documented descendants of Jean Nougaret, show that rod function is present, although subnormal, and that there is slight impairment of cone function. The data also suggest that these abnormalities can be simulated by light-adapting the normal retina, compatible with the proposal that the rod transducin encoded by the mutant gene is constitutively active and that the night blindness results from partial desensitization of rods caused by the constitutive activity.

Adult↗
PubMed1998

Histopathologic and immunohistochemical study of dominant cone degeneration.

PURPOSE: To report the histopathologic and immunohistochemical findings in autosomal dominant cone degeneration. METHODS: The autopsy eyes of a 75-year-old man with autosomal dominant cone degeneration were studied with both light and electron microscopy. In addition, immunofluorescent studies using antibodies to cone opsins and cone alpha transducin were performed. RESULTS: Histopathologic examination of the fovea disclosed loss of photoreceptors and attenuated retinal pigment epithelium. Reduced numbers of cones could be seen in the parafovea, and only occasional cones were visible in the periphery; rods were preserved in the periphery. CONCLUSION: The histopathologic and immunohistochemical findings in this case of dominantly inherited cone degeneration correlate well with the loss of cone function and preservation of normal or nearly normal rod function upon clinical examination. This condition affects red, green, and blue cones.

Aged↗
PubMed1998

Recessive mutations in the gene encoding the tubby-like protein TULP1 in patients with retinitis pigmentosa.

A recessive mutation in the tub gene causes obesity, deafness and retinal degeneration in tubby mice. The tub gene is a member of a family of tubby-like genes (TULPs) that encode proteins of unknown function. Members of this family have been identified in plants, vertebrates and invertebrates. The TULP proteins share a conserved carboxy-terminal region of approximately 200 amino-acid residues. Here we report the analysis of the human gene TULP1, which is expressed specifically in the retina. Upon analysing 162 patients with nonsyndromic recessive retinitis pigmentosa (RP) and 374 simplex cases of RP, we found two who were compound heterozygotes for mutations that cosegregated with disease in the respective families. Three of the mutations are missense changes affecting the conserved C-terminal region; the fourth mutation affects a splice donor site upstream of this region. Our data suggest that mutations in TULP1 are a rare cause of recessive RP and indicate that TULP1 has an essential role in the physiology of photoreceptors.

Amino Acid Sequence↗
PubMed1998

Evaluation of the human arrestin gene in patients with retinitis pigmentosa and stationary night blindness.

PURPOSE: To establish the DNA sequence of the coding regions of the human arrestin locus and to determine whether defects in this sequence are present among patients with retinitis pigmentosa (RP) or types of stationary night blindness in addition to Oguchi disease. METHODS: The human genomic locus encoding arrestin was cloned in bacteriophage and P1 vectors. The sequence of the intron DNA flanking each exon was determined from these clones. Single-strand conformation polymorphism analysis and direct genomic sequencing techniques were used to screen 272 unrelated patients, comprising 177 patients with autosomal dominant RP, 85 with recessive RP, and 10 with stationary night blindness. RESULTS: The arrestin gene is divided into 16 exons ranging in size from 10 bp to 194 bp, with the open reading frame spanning exons 2 through 16. The authors identified several discrepancies between the genomic sequence the authors obtained and the previously published cDNA and genomic sequences. In the set of patients with dominant RP, the authors found one of three heterozygous missense changes (Arg84Cys, Thr125Met, and Val378Ile) in each of four unrelated patients; none of these changes cosegregated with disease in the respective families. In the set of patients with recessive RP, the authors found one of two heterozygous missense changes in each of two unrelated patients with recessive RP (Pro364Leu and Arg384Cys). One of the patients was the offspring of a consanguineous marriage; because the Arg384Cys change in him was heterozygous, it is unlikely to have been the cause of his RP. Cosegregation studies could not be performed on the patient with the Pro364Leu change. The authors confirmed the existence of two previously described polymorphisms (Ile76Val and a multiallelic polymorphism at codon 403), and the authors identified several silent polymorphisms and rare sequence variants. No sequence changes, other than polymorphic changes also found in some patients with RP, were identified in the patients with stationary night blindness. CONCLUSIONS: We found no evidence that mutations in arrestin are a cause of RP or stationary night blindness other than Oguchi disease. According to the genomic sequence obtained, a region in exon 8 that has been postulated to represent the site of interaction between arrestin and rhodopsin is 100% conserved between humans and all other mammals studied to date.

Arrestin↗
PubMed1997

ERG abnormalities in relation to histopathologic findings in vitiligo mutant mice.

The vitiligo, mivit, mutation has several prenatal and perinatal effects on development of the retinal pigment epithelium, and later, leads to extensive, progressive degeneration of photoreceptor cells in the neural retina of homozygous affected mice. The aim of the present study was to determine by functional criteria how early can abnormalities be detected in the neural retina. Electroretinograms (ERGs) were correlated with histopathological findings in the same animals. Congenic homozygous mutants, heterozygotes, and homozygous wild-type mice were studied at 2, 3, 6, 24 and 56 weeks of age, the same animals being tested serially at the three older time points. The nontested eye of each animal was embedded in Epon and sectioned at 1 micron for light microscopic study. ERG recordings from vitiligo homozygotes differed from heterozygous and wild-type mice, but the latter two groups did not differ from each other. As early as two weeks of age, homozygous mutants showed a significant reduction of rod dominated maximum ERG a-wave and b-wave amplitude. ERG b-wave sensitivity (sigma) was significantly reduced, and ERG implicit times were delayed for homozygous mutants at 3 (a-wave) and 6 (b-wave) weeks of age. This is the first study to report reduced and delayed ERG a-waves and b-waves in this animal model, like the early functional abnormalities in human retinitis pigmentosa, and also the first to show short and disoriented rod outer segments, beginning retinal separation from the pigment epithelium, and a few macrophage-like cells already present in the subretinal space at 2 weeks of age (in three of four homozygous mutant eyes examined). Given these early functional and structural abnormalities in the neural retina, it remains to be determined whether the mi gene targets the retinal pigment epithelial cell, the photoreceptor cell, or both.

Aging↗
PubMed1997

Evaluation of the rhodopsin kinase gene in patients with retinitis pigmentosa.

We explored the possibility that defects in the rhodopsin kinase gene might cause retinitis pigmentosa (RP) by evaluating 160 unrelated cases with dominant RP and 151 unrelated cases with recessive RP. One of five missense changes was discovered in each of six cases of dominant RP, but none of the missense changes cosegregated with disease among relatives. Heterozygous missense changes were found in two cases of recessive RP, and a heterozygous frameshift mutation was found in one additional case of recessive RP. Although the same DNA sequence alterations could be found heterozygously in the only affected sibling of each index case of recessive RP, no defect could be found in the other allele. Hence, none of the changes found in the cases of dominant or recessive RP was proven to be a cause of RP. The data indicate that defects in the rhodopsin kinase gene causing RP are either rare or nonexistent.

Codon↗
PubMed1997

Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness.

Oguchi disease is a recessively inherited form of stationary night blindness due to malfunction of the rod photoreceptor mechanism. Patients with this disease show a distinctive golden-brown colour of the fundus that occurs as the retina adapts to light, called the Mizuo phenomenon. Recently a defect in arrestin, a member of the rod phototransduction pathway, was found to cause this disease in some Japanese patients. As rhodopsin kinase works with arrestin in shutting off rhodopsin after it has been activated by a photon of light, it is reasonable to propose that some cases of Oguchi disease might be caused by defects in rhodopsin kinase. This report describes an analysis of the arrestin and rhodopsin kinase genes in three unrelated cases of Oguchi disease. No defects in arrestin were detected, but all three cases had mutations in the rhodopsin kinase gene. Two cases were found to be homozygous for a deletion encompassing exon 5, predicted to lead to a nonfunctional protein. The third case was a compound heterozygote with two allelic mutations, a missense mutation (Val380Asp) affecting a residue in the catalytic domain, and a frameshift mutation (Ser536(4-bp del)) resulting in truncation of the carboxy terminus. Our results indicate that null mutations in the rhodopsin kinase gene are a cause of Oguchi disease and extend the known genetic heterogeneity in congenital stationary night blindness.

Alleles↗