Publications by authors named "Eliot L Berson"

71 Publications

Association of Vitamin A Supplementation With Disease Course in Children With Retinitis Pigmentosa.

JAMA Ophthalmol 2018 05;136(5):490-495

Berman-Gund Laboratory for the Study of Retinal Degenerations, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston.

Importance: While oral vitamin A supplementation is considered to potentially slow loss of retinal function in adults with retinitis pigmentosa and normal liver function, little data from children with this disease are available.

Objective: To compare disease courses in children with retinitis pigmentosa taking or not taking vitamin A supplementation.

Design, Setting, And Participants: Retrospective, nonrandomized comparison of vitamin A and control cohorts followed up for a mean of 4 to 5 years by the Electroretinography Service of the Massachusetts Eye and Ear Infirmary. The study included children with different genetic types of typical retinitis pigmentosa: 55 taking vitamin A and 25 not taking vitamin A. The dates for patient evaluations ranged from June 1976 to July 2016, and the data analysis occurred in October 2016.

Interventions: Age-adjusted dose of oral vitamin A palmitate (≤15 000 IU/d).

Main Outcomes And Measures: Mean exponential rates of change of full-field cone electroretinogram amplitude to 30-Hz flashes estimated by repeated-measures longitudinal regression without and with adjusting for potential confounders.

Results: Of the 55 children in the vitamin A cohort, 38 (69%) were male; the mean [SD] age was 9.1 [1.9] years; and 48 (87%) were white , 6 (11%) were Asian, and 1 (2%) was black. Of the 25 members of the control cohort, 19 (76%) were male; the mean [SD] age was 9.2 [1.7] years; and 25 (100%) were white. The estimated mean rates of change with the unadjusted model were -0.0713 loge unit/y (-6.9% per year) for the vitamin A cohort and -0.1419 loge unit per year (-13.2% per year) for the control cohort (difference, 0.0706 loge unit per year; 95% CI for the difference, 0.0149-0.1263 loge unit per year; P = .01). The adjusted model confirmed a slower mean rate of decline in the vitamin A cohort (difference, 0.0771 loge-unit per year; 95% CI for the difference, 0.0191-0.1350 loge-unit per year; P = .009). With respect to ocular safety, the mean exponential rates of change of visual field area and visual acuity and the incidences of falling to a visual field diameter of 20° or less or a visual acuity of 20/200 or less in at least 1 eye did not differ by cohort.

Conclusions And Relevance: A vitamin A palmitate supplement was associated with a slower loss of cone electroretinogram amplitude in children with retinitis pigmentosa. Although the relatively small-sample, retrospective, nonrandomized design does not allow a test of causation and is subject to possible biases, these findings support consideration of an age-adjusted dose of vitamin A in the management of most children with the common forms of retinitis pigmentosa.
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http://dx.doi.org/10.1001/jamaophthalmol.2018.0590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876883PMC
May 2018

The risk of pedestrian collisions with peripheral visual field loss.

J Vis 2016 12;16(15)

Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA;

Patients with peripheral field loss complain of colliding with other pedestrians in open-space environments such as shopping malls. Field expansion devices (e.g., prisms) can create artificial peripheral islands of vision. We investigated the visual angle at which these islands can be most effective for avoiding pedestrian collisions, by modeling the collision risk density as a function of bearing angle of pedestrians relative to the patient. Pedestrians at all possible locations were assumed to be moving in all directions with equal probability within a reasonable range of walking speeds. The risk density was found to be highly anisotropic. It peaked at ≈45° eccentricity. Increasing pedestrian speed range shifted the risk to higher eccentricities. The risk density is independent of time to collision. The model results were compared to the binocular residual peripheral island locations of 42 patients with forms of retinitis pigmentosa. The natural residual island prevalence also peaked nasally at about 45° but temporally at about 75°. This asymmetry resulted in a complementary coverage of the binocular field of view. Natural residual binocular island eccentricities seem well matched to the collision-risk density function, optimizing detection of other walking pedestrians (nasally) and of faster hazards (temporally). Field expansion prism devices will be most effective if they can create artificial peripheral islands at about 45° eccentricities. The collision risk and residual island findings raise interesting questions about normal visual development.
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http://dx.doi.org/10.1167/16.15.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142795PMC
December 2016

Visual Function in Carriers of X-Linked Retinitis Pigmentosa.

Ophthalmology 2015 Sep 2;122(9):1899-906. Epub 2015 Jul 2.

Berman-Gund Laboratory for the Study of Retinal Degenerations, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, Massachusetts.

Purpose: To determine the frequency and severity of visual function loss in female carriers of X-linked retinitis pigmentosa (XLRP).

Design: Case series.

Participants: Two hundred seventy-six XLRP carriers with cross-sectional data (n = 242) and longitudinal data (n = 34; median follow-up, 16 years; follow-up range, 3-37 years). Half of the carriers were from RPGR- or RP2-genotyped families.

Methods: Retrospective medical records review.

Main Outcome Measures: Visual acuities, visual field areas, final dark adaptation thresholds, and full-field electroretinography (ERG) responses to 0.5-Hz and 30-Hz flashes.

Results: In genotyped families, 40% of carriers showed a baseline abnormality on at least 1 of 3 psychophysical tests. There was a wide range of function among carriers. For example, 3 of 121 (2%) genotyped carriers were legally blind because of poor visual acuity, some as young as 35 years. Visual fields were less affected than visual acuity. In all carriers, the average ERG amplitude to 30-Hz flashes was approximately 50% of normal, and the average exponential rate of amplitude loss over time was half that of XLRP males (3.7%/year vs. 7.4%/year, respectively). Among obligate carriers with affected fathers, sons, or both, 53 of 55 (96%) had abnormal baseline ERG results. Some carriers who initially had completely normal fundi in both eyes went on to experience moderately decreased vision, although not legal blindness. Among carriers with RPGR mutations, those with mutations in ORF15, compared with those in exons 1-14, had worse final dark adaptation thresholds and lower 0.5-Hz and 30-Hz ERG amplitudes.

Conclusions: Most carriers of XLRP had mildly or moderately reduced visual function but rarely became legally blind. In most cases, obligate carriers could be identified by ERG testing. Carriers of RPGR ORF15 mutations tended to have worse visual function than carriers of RPGR exon 1 through 14 mutations. Because XLRP carrier ERG amplitudes and decay rates over time were on average half of those of affected men, these observations were consistent with the Lyon hypothesis of random X-inactivation.
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http://dx.doi.org/10.1016/j.ophtha.2015.05.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562908PMC
September 2015

Targeted exon sequencing in Usher syndrome type I.

Invest Ophthalmol Vis Sci 2014 Dec 2;55(12):8488-96. Epub 2014 Dec 2.

Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States.

Purpose: Patients with Usher syndrome type I (USH1) have retinitis pigmentosa, profound congenital hearing loss, and vestibular ataxia. This syndrome is currently thought to be associated with at least six genes, which are encoded by over 180 exons. Here, we present the use of state-of-the-art techniques in the molecular diagnosis of a cohort of 47 USH1 probands.

Methods: The cohort was studied with selective exon capture and next-generation sequencing of currently known inherited retinal degeneration genes, comparative genomic hybridization, and Sanger sequencing of new USH1 exons identified by human retinal transcriptome analysis.

Results: With this approach, we were able to genetically solve 14 of the 47 probands by confirming the biallelic inheritance of mutations. We detected two likely pathogenic variants in an additional 19 patients, for whom family members were not available for cosegregation analysis to confirm biallelic inheritance. Ten patients, in addition to primary disease-causing mutations, carried rare likely pathogenic USH1 alleles or variants in other genes associated with deaf-blindness, which may influence disease phenotype. Twenty-one of the identified mutations were novel among the 33 definite or likely solved patients. Here, we also present a clinical description of the studied cohort at their initial visits.

Conclusions: We found a remarkable genetic heterogeneity in the studied USH1 cohort with multiplicity of mutations, of which many were novel. No obvious influence of genotype on phenotype was found, possibly due to small sample sizes of the genotypes under study.
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http://dx.doi.org/10.1167/iovs.14-15169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280089PMC
December 2014

Two specific mutations are prevalent causes of recessive retinitis pigmentosa in North American patients of Jewish ancestry.

Genet Med 2015 Apr 25;17(4):285-90. Epub 2014 Sep 25.

Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

Purpose: Retinitis pigmentosa is a Mendelian disease with a very elevated genetic heterogeneity. Most mutations are responsible for less than 1% of cases, making molecular diagnosis a multigene screening procedure. In this study, we assessed whether direct testing of specific alleles could be a valuable screening approach in cases characterized by prevalent founder mutations.

Methods: We screened 275 North American patients with recessive/isolate retinitis pigmentosa for two mutations: an Alu insertion in the MAK gene and the p.Lys42Glu missense in the DHDDS gene. All patients were unrelated; 35 reported Jewish ancestry and the remainder reported mixed ethnicity.

Results: We identified the MAK and DHDDS mutations homozygously in only 2.1% and 0.8%, respectively, of patients of mixed ethnicity, but in 25.7% and 8.6%, respectively, of cases reporting Jewish ancestry. Haplotype analyses revealed that inheritance of the MAK mutation was attributable to a founder effect.

Conclusion: In contrast to most mutations associated with retinitis pigmentosa-which are, in general, extremely rare-the two alleles investigated here cause disease in approximately one-third of North American patients reporting Jewish ancestry. Therefore, their screening constitutes an alternative procedure to large-scale tests for patients belonging to this ethnic group, especially in time-sensitive situations.
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http://dx.doi.org/10.1038/gim.2014.132DOI Listing
April 2015

The relationship of central foveal thickness to urinary iodine concentration in retinitis pigmentosa with or without cystoid macular edema.

JAMA Ophthalmol 2014 Oct;132(10):1209-14

Berman-Gund Laboratory for the Study of Retinal Degenerations, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston.

Importance: Current treatments for cystoid macular edema (CME) in retinitis pigmentosa (RP) are not always effective, may lead to adverse effects, and may not restore visual acuity. The present research lays the rationale for evaluating whether an iodine supplement could reduce CME in RP.

Objective: To determine whether central foveal thickness (CFT) in the presence of CME is related to dietary iodine intake inferred from urinary iodine concentration (UIC) in nonsmoking adults with RP.

Design, Setting, And Participants: We performed a cross-sectional observational study of 212 nonsmoking patients aged 18 to 69 years referred to our institution for RP with visual acuity of no worse than 20/200 in at least 1 eye.

Exposure: Retinitis pigmentosa with or without CME.

Main Outcomes And Measures: With the eye as the unit of analysis, the relationship of log CFT measured by optical coherence tomography to UIC measured from multiple spot samples and represented as a 3-level classification variable (<100, 100-199, and ≥200 µg/L), assigning greater weight to patients with more reliable UIC estimates.

Results: Analyses were limited to 199 patients after excluding 11 who failed to return urine samples for measuring UIC and 2 outliers for UIC. Of the 199 patients, 36.2% had CME in 1 or both eyes. Although log CFT was inversely related to UIC based on findings from all eyes (P = .02), regression of log CFT on UIC separately for eyes with and without CME showed a strong inverse significant relationship for the former group (P < .001) and no significant relationship for the latter group (P = .66) as tested. For the eyes with CME, CFT ranged from a geometric mean of 267 µm for a median UIC of less than 100 µg/L to a geometric mean of 172 µm for a median UIC of 200 µg/L or greater. In contrast, we found no significant association between CME prevalence and UIC based on the entire sample as tested (odds ratio, 1.01 [95% CI, 0.38-2.67]; P = .99).

Conclusions And Relevance: A higher UIC in nonsmoking adults with RP was significantly associated with less central foveal swelling in eyes with CME. Additional study is required to determine whether an iodine supplement can limit or reduce the extent of CME in patients with RP.
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http://dx.doi.org/10.1001/jamaophthalmol.2014.1726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192011PMC
October 2014

Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa.

Mol Vis 2014 18;20:843-51. Epub 2014 Jun 18.

Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

Purpose: Mutations in genes encoding proteins from the tri-snRNP complex of the spliceosome account for more than 12% of cases of autosomal dominant retinitis pigmentosa (adRP). Although the exact mechanism by which splicing factor defects trigger photoreceptor death is not completely clear, their role in retinitis pigmentosa has been demonstrated by several genetic and functional studies. To test for possible novel associations between splicing factors and adRP, we screened four tri-snRNP splicing factor genes (EFTUD2, PRPF4, NHP2L1, and AAR2) as candidate disease genes.

Methods: We screened up to 303 patients with adRP from Europe and North America who did not carry known RP mutations. Exon-PCR and Sanger methods were used to sequence the NHP2L1 and AAR2 genes, while the sequences of EFTUD2 and PRPF4 were obtained by using long-range PCRs spanning coding and non-coding regions followed by next-generation sequencing.

Results: We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified. In one other patient we identified a novel nucleotide substitution in the 5' untranslated region (UTR) of NHP2L1, which did not segregate with the disease in the family.

Conclusions: The absence of clearly pathogenic mutations in the candidate genes screened in our cohort suggests that EFTUD2, PRPF4, NHP2L1, and AAR2 are either not involved in adRP or are associated with the disease in rare instances, at least as observed in this study in patients of European and North American origin.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063357PMC
September 2014

Molecular genetics of FAM161A in North American patients with early-onset retinitis pigmentosa.

PLoS One 2014 20;9(3):e92479. Epub 2014 Mar 20.

The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America.

Retinitis pigmentosa (RP) is a hereditary disease that leads to the progressive degeneration of retinal photoreceptor cells and to blindness. It is caused by mutations in several distinct genes, including the ciliary gene FAM161A, which is associated with a recessive form of this disorder. Recent investigations have revealed that defects in FAM161A represent a rather prevalent cause of hereditary blindness in Israel and the Palestinian territories, whereas they seem to be rarely present within patients from Germany. Genetic or clinical data are currently not available for other countries. In this work, we screened a cohort of patients with recessive RP from North America to determine the frequency of FAM161A mutations in this ethnically-mixed population and to assess the phenotype of positive cases. Out of 273 unrelated patients, only 3 subjects had defects in FAM161A. A fourth positive patient, the sister of one of these index cases, was also identified following pedigree analysis. They were all homozygous for the p.T452Sfx3 mutation, which was previously reported as a founder DNA variant in the Israeli and Palestinian populations. Analysis of cultured lymphoblasts from patients revealed that mutant FAM161A transcripts were actively degraded by nonsense-mediated mRNA decay. Electroretinographic testing showed 30 Hz cone flicker responses in the range of 0.10 to 0.60 microvolts in all cases at their first visit (age 12 to 23) (lower norm  =  50 μV) and of 0.06 to 0.32 microvolts at their most recent examination (age 27 to 43), revealing an early-onset of this progressive disease. Our data indicate that mutations in FAM161A are responsible for 1% of recessive RP cases in North America, similar to the prevalence detected in Germany and unlike the data from Israel and the Palestinian territories. We also show that, at the molecular level, the disease is likely caused by FAM161A protein deficiency.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092479PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961368PMC
November 2014

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene.

Proc Natl Acad Sci U S A 2013 Oct 16;110(40):16139-44. Epub 2013 Sep 16.

Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland.

We performed whole genome sequencing in 16 unrelated patients with autosomal recessive retinitis pigmentosa (ARRP), a disease characterized by progressive retinal degeneration and caused by mutations in over 50 genes, in search of pathogenic DNA variants. Eight patients were from North America, whereas eight were Japanese, a population for which ARRP seems to have different genetic drivers. Using a specific workflow, we assessed both the coding and noncoding regions of the human genome, including the evaluation of highly polymorphic SNPs, structural and copy number variations, as well as 69 control genomes sequenced by the same procedures. We detected homozygous or compound heterozygous mutations in 7 genes associated with ARRP (USH2A, RDH12, CNGB1, EYS, PDE6B, DFNB31, and CERKL) in eight patients, three Japanese and five Americans. Fourteen of the 16 mutant alleles identified were previously unknown. Among these, there was a 2.3-kb deletion in USH2A and an inverted duplication of ~446 kb in EYS, which would have likely escaped conventional screening techniques or exome sequencing. Moreover, in another Japanese patient, we identified a homozygous frameshift (p.L206fs), absent in more than 2,500 chromosomes from ethnically matched controls, in the ciliary gene NEK2, encoding a serine/threonine-protein kinase. Inactivation of this gene in zebrafish induced retinal photoreceptor defects that were rescued by human NEK2 mRNA. In addition to identifying a previously undescribed ARRP gene, our study highlights the importance of rare structural DNA variations in Mendelian diseases and advocates the need for screening approaches that transcend the analysis of the coding sequences of the human genome.
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http://dx.doi.org/10.1073/pnas.1308243110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791719PMC
October 2013

Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations.

Hum Mutat 2013 Nov 17;34(11):1537-1546. Epub 2013 Sep 17.

Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.

This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ∼2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.
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http://dx.doi.org/10.1002/humu.22398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337959PMC
November 2013

Spinocerebellar ataxia type 7: clinical course, phenotype-genotype correlations, and neuropathology.

Cerebellum 2013 Apr;12(2):176-93

Ataxia Unit, Cognitive and Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Suite 340, Charles River Plaza South, 175 Cambridge Street, Boston, MA 02114, USA.

Spinocerebellar ataxia type 7 is a neurodegenerative polyglutamine disease characterized by ataxia and retinal degeneration. The longitudinal course is unknown, and relationships between repeat expansion, clinical manifestations, and neuropathology remain uncertain. We followed 16 affected individuals of a 61-member kindred over 27 years with electroretinograms, neurological examinations including the Brief Ataxia Rating Scale, neuroimaging in five, and autopsy in four cases. We identified four stages of the illness: Stage 0, gene-positive but phenotypically silent; Stage 1, no symptoms, but hyperreflexia and/or abnormal electroretinograms; Stage 2, symptoms and signs progress modestly; and Stage 3, rapid clinical progression. CAG repeat length correlated inversely with age of onset of visual or motor signs (r = -0.74, p = 0.002). Stage 3 rate of progression did not differ between cases (p = 0.18). Electroretinograms correlated with Brief Ataxia Rating Scale score and were a biomarker of disease onset and progression. All symptomatic patients developed gait ataxia, extremity dysmetria, dysarthria, dysrhythmia, and oculomotor abnormalities. Funduscopy revealed pale optic discs and pigmentary disturbances. Visual acuity declined to blindness in those with longer CAG expansions. Hyperreflexia was present from Stage 1 onwards. Restless legs syndrome and sensory impairment were common. Neuropathological hallmarks were neuronal loss in cerebellar cortex, deep cerebellar nuclei, inferior olive, and anterior horns of the spinal cord, and axonal loss in spinocerebellar tracts, dorsal nerve roots, and posterior columns. Retinal pathology included photoreceptor degeneration and disruption of retinal pigment epithelium. Spinocerebellar ataxia type 7 evolves through four clinical stages; neuropathological findings underlie the clinical presentation; electroretinograms are a potential biomarker of disease progression.
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http://dx.doi.org/10.1007/s12311-012-0412-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562565PMC
April 2013

NMNAT1 mutations cause Leber congenital amaurosis.

Nat Genet 2012 Sep 29;44(9):1040-5. Epub 2012 Jul 29.

Department of Pediatrics, Division of Human Genetics, The Children's Hospital of Philadelphia, Pennsylvania, USA.

Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss(1,2). Two-thirds of LCA cases are caused by mutations in 17 known disease-associated genes(3) (Retinal Information Network (RetNet)). Using exome sequencing we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 that is likely to be disease causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in the kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD(+)) biosynthesis(4,5). Functional studies showed that the p.Val9Met alteration decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated families with LCA identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease in humans and indicate that NMNAT1 mutations cause LCA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3454532PMC
http://dx.doi.org/10.1038/ng.2361DOI Listing
September 2012

Genotype-phenotype correlations in Bardet-Biedl syndrome.

Arch Ophthalmol 2012 Jul;130(7):901-7

Berman-Gund Laboratory for the Study of Retinal Degenerations, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.

Objective: To determine whether mutations in different Bardet-Biedl syndrome (BBS) genes result in different ocular phenotypes.

Methods: Thirty-seven patients from 31 families were enrolled who met the clinical criteria for BBS and for whom a BBS mutation had been identified. Seventeen patients harbored mutations in BBS1, 10 in BBS10, and 10 in other genes (BBS2, BBS3, BBS5, BBS7, and BBS12). All the patients underwent ocular examination; 36 patients had computerized full-field electroretinograms (ERGs).

Results: Visual acuity was significantly better in BBS1 patients than in patients with other BBS mutations (P=.01), and a larger proportion of BBS1 patients had good (≥20/50) visual acuity (P=.01). The ERG amplitudes were significantly higher in BBS1 patients than in patients with other BBS mutations in response to 0.5-Hz and 30-Hz flashes (P<.001 for both). All the BBS1 patients harbored at least 1 missense mutation compared with only 45% of patients with mutations in other BBS genes (P<.001); the rest harbored only null alleles. However, multivariate analysis demonstrated that visual acuity or ERG amplitude did not depend on the type of mutation present (missense or null) when controlling for BBS gene. Prevalences of bone spicule pigmentation and cataract were comparable in BBS subtypes.

Conclusions: Patients with BBS1 mutations had a milder phenotype than did patients with mutations in other BBS genes. Clinically, this manifested as significantly better visual acuity and larger ERG amplitudes.

Clinical Relevance: These phenotypic differences can help guide genetic testing and genetic counseling for patients with this syndrome.
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http://dx.doi.org/10.1001/archophthalmol.2012.89DOI Listing
July 2012

ω-3 intake and visual acuity in patients with retinitis pigmentosa receiving vitamin A.

Arch Ophthalmol 2012 Jun;130(6):707-11

Objective: To evaluate whether a diet high in long chain ω-3 fatty acids can slow the rate of visual acuity loss among patients with retinitis pigmentosa receiving vitamin A palmitate.

Methods: We calculated dietary intake from questionnaires completed annually by 357 adult patients from 3 randomized trials who were all receiving vitamin A, 15 000 IU/d, for 4 to 6 years. Rates of visual acuity decline were compared between those with high (≥0.20 g/d) vs low (<0.20 g/d) ω-3 intake. Analyses took age into account.

Results: Mean rates of decline of acuity were slower among those with high ω-3 intake: Early Treatment Diabetic Retinopathy Study distance acuity: high intake=0.59 letter per year, low intake=1.00 letter per year,P=.001; Snellen retinal acuity: high intake=1.5% per year, low intake=2.8% per year, P=.03.

Conclusions: We conclude that mean annual rates of decline in distance and retinal visual acuities in adults with retinitis pigmentosa receiving vitamin A, 15 000 IU/d,are slower over 4 to 6 years among those consuming a diet rich in ω-3 fatty acids. To our knowledge, this is the first report that nutritional intake can modify the rate of decline of visual acuity in retinitis pigmentosa.
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http://dx.doi.org/10.1001/archophthalmol.2011.2580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552384PMC
June 2012

Disease course of patients with unilateral pigmentary retinopathy.

Invest Ophthalmol Vis Sci 2011 Nov 29;52(12):9244-9. Epub 2011 Nov 29.

Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA.

Purpose: To evaluate the change in ocular function by eye in patients with unilateral pigmentary retinopathy.

Methods: Longitudinal regression was used to estimate mean exponential rates of change in Goldmann visual field area (V4e white test light) and in full-field electroretinogram (ERG) amplitudes to 0.5- and 30-Hz white flashes in 15 patients with unilateral pigmentary retinopathy. Snellen visual acuity was assessed case by case.

Results: Mean annual rates of change for the affected eyes were -4.9% for visual field area, -4.7% for ERG amplitude to 0.5-Hz flashes, and -4.6% for ERG amplitude to 30-Hz flashes. All three rates were faster than the corresponding age-related rates of change for the fellow normal eyes (P = 0.0006, P = 0.003, P = 0.03, respectively). An initial cone ERG implicit time to 30-Hz flashes in affected eyes ≥ 40 ms predicted a faster mean rate of decline of visual field area and of ERG amplitude to 0.5- and 30-Hz flashes (P < 0.0001 for all three measures). The visual acuity of affected eyes was more likely to decrease in patients presenting at >35 years of age than in patients presenting at a younger age (P = 0.0004).

Conclusions: The affected eye in unilateral pigmentary retinopathy shows a progressive loss of peripheral retinal function that cannot be attributed to aging alone and that is faster in eyes with a more prolonged initial cone ERG implicit time. Patients presenting at >35 years of age are at greater risk for losing visual acuity.
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http://dx.doi.org/10.1167/iovs.11-7892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302431PMC
November 2011

Histopathology and functional correlations in a patient with a mutation in RPE65, the gene for retinol isomerase.

Invest Ophthalmol Vis Sci 2011 Oct 28;52(11):8381-92. Epub 2011 Oct 28.

Cole Eye Institute, Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195, USA.

Purpose: Here the authors describe the structural features of the retina and retinal pigment epithelium (RPE) in postmortem donor eyes of a 56-year-old patient with a homozygous missense RPE65 mutation (Ala132Thr) and correlate the pathology with the patient's visual function last measured at age 51.

Methods: Eyes were enucleated within 13.5 hours after death. Representative areas from the macula and periphery were processed for light and electron microscopy. Immunofluorescence was used to localize the distribution of RPE65, rhodopsin, and cone arrestin. The autofluorescence in the RPE was compared with that of two normal eyes from age-similar donors.

Results: Histologic examination revealed the loss of rods and cones across most areas of the retina, attenuated retinal vessels, and RPE thinning in both eyes. A small number of highly disorganized cones were present in the macula that showed simultaneous labeling with cone arrestin and red/green or blue opsin. RPE65 immunoreactivity and RPE autofluorescence were reduced compared with control eyes in all areas studied. Rhodopsin labeling was observed in rods in the far periphery. The optic nerve showed a reduced number of axons.

Conclusions: The clinical findings of reduced visual acuity, constricted fields, and reduced electroretinograms (ERGs) 5 years before death correlated with the small number of cones present in the macula and the extensive loss of photoreceptors in the periphery. The absence of autofluorescence in the RPE suggests that photoreceptor cells were probably missing across the retina for extended periods of time. Possible mechanisms that could lead to photoreceptor cell death are discussed.
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http://dx.doi.org/10.1167/iovs.11-7973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208160PMC
October 2011

Molecular analysis of Bardet-Biedl syndrome families: report of 21 novel mutations in 10 genes.

Invest Ophthalmol Vis Sci 2011 Jul 18;52(8):5317-24. Epub 2011 Jul 18.

Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20852, USA.

Purpose: Bardet-Biedl syndrome (BBS) is genetically heterogeneous with 15 BBS genes currently identified, accounting for approximately 70% of cases. The aim of our study was to define further the spectrum of BBS mutations in a cohort of 44 European-derived American, 8 Tunisian, 1 Arabic, and 2 Pakistani families (55 families in total) with BBS.

Methods: A total of 142 exons of the first 12 BBS-causing genes were screened by dideoxy sequencing. Cases in which no mutations were found were then screened for BBS13, BBS14, BBS15, RPGRIP1L, CC2D2A, NPHP3, TMEM67, and INPP5E.

Results: Forty-three mutations, including 8 frameshift mutations, 10 nonsense mutations, 4 splice site mutations, 1 deletion, and 20 potentially or probably pathogenic missense variations, were identified in 46 of the 55 families studied (84%). Of these, 21 (2 frameshift mutations, 4 nonsense mutations, 4 splice site mutations, 1 deletion, and 10 missense variations) were novel. The molecular genetic findings raised the possibility of triallelic inheritance in 7 Caucasian families, 1 Arabian family, and 1 Tunisian patient. No mutations were detected for BBS4, BBS11, BBS13, BBS14, BBS15, RPGRIP1L, CC2D2A, NPHP3, TMEM67, or INPP5E.

Conclusions: This mutational analysis extends the spectrum of known BBS mutations. Identification of 21 novel mutations highlights the genetic heterogeneity of this disorder. Differences in European and Tunisian patients, including the high frequency of the M390R mutation in Europeans, emphasize the population specificity of BBS mutations with potential diagnostic implications. The existence of some BBS cases without mutations in any currently identified BBS genes suggests further genetic heterogeneity.
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http://dx.doi.org/10.1167/iovs.11-7554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176075PMC
July 2011

Next generation sequencing of pooled samples reveals new SNRNP200 mutations associated with retinitis pigmentosa.

Hum Mutat 2011 Jun 24;32(6):E2246-58. Epub 2011 Feb 24.

Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

The gene SNRNP200 is composed of 45 exons and encodes a protein essential for pre-mRNA splicing, the 200 kDa helicase hBrr2. Two mutations in SNRNP200 have recently been associated with autosomal dominant retinitis pigmentosa (adRP), a retinal degenerative disease, in two families from China. In this work we analyzed the entire 35-Kb SNRNP200 genomic region in a cohort of 96 unrelated North American patients with adRP. To complete this large-scale sequencing project, we performed ultra high-throughput sequencing of pooled, untagged PCR products. We then validated the detected DNA changes by Sanger sequencing of individual samples from this cohort and from an additional one of 95 patients. One of the two previously known mutations (p.S1087L) was identified in 3 patients, while 4 new missense changes (p.R681C, p.R681H, p.V683L, p.Y689C) affecting highly conserved codons were identified in 6 unrelated individuals, indicating that the prevalence of SNRNP200-associated adRP is relatively high. We also took advantage of this research to evaluate the pool-and-sequence method, especially with respect to the generation of false positive and negative results. We conclude that, although this strategy can be adopted for rapid discovery of new disease-associated variants, it still requires extensive validation to be used in routine DNA screenings.
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http://dx.doi.org/10.1002/humu.21485DOI Listing
June 2011

A missense mutation in PRPF6 causes impairment of pre-mRNA splicing and autosomal-dominant retinitis pigmentosa.

Am J Hum Genet 2011 May 5;88(5):643-9. Epub 2011 May 5.

Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

Retinitis pigmentosa (RP) is an inherited form of retinal degeneration that leads to progressive visual-field constriction and blindness. Although the disease manifests only in the retina, mutations in ubiquitously expressed genes associated with the tri-snRNP complex of the spliceosome have been identified in patients with dominantly inherited RP. We screened for mutations in PRPF6 (NM_012469.3), a gene on chromosome 20q13.33 encoding an essential protein for tri-snRNP assembly and stability, in 188 unrelated patients with autosomal-dominant RP and identified a missense mutation, c.2185C>T (p.Arg729Trp). This change affected a residue that is conserved from humans to yeast and cosegregated with the disease in the family in which it was identified. Lymphoblasts derived from patients with this mutation showed abnormal localization of endogenous PRPF6 within the nucleus. Specifically, this protein accumulated in the Cajal bodies, indicating a possible impairment in the tri-snRNP assembly or recycling. Expression of GFP-tagged PRPF6 in HeLa cells showed that this phenomenon depended exclusively on the mutated form of the protein. Furthermore, analysis of endogenous transcripts in cells from patients revealed intron retention for pre-mRNA bearing specific splicing signals, according to the same pattern displayed by lymphoblasts with mutations in other PRPF genes. Our results identify PRPF6 as the sixth gene involved in pre-mRNA splicing and dominant RP, corroborating the hypothesis that deficiencies in the spliceosome play an important role in the molecular pathology of this disease.
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http://dx.doi.org/10.1016/j.ajhg.2011.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146730PMC
May 2011

PRPF mutations are associated with generalized defects in spliceosome formation and pre-mRNA splicing in patients with retinitis pigmentosa.

Hum Mol Genet 2011 Jun 5;20(11):2116-30. Epub 2011 Mar 5.

Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Proteins PRPF31, PRPF3 and PRPF8 (RP-PRPFs) are ubiquitously expressed components of the spliceosome, a macromolecular complex that processes nearly all pre-mRNAs. Although these spliceosomal proteins are conserved in eukaryotes and are essential for survival, heterozygous mutations in human RP-PRPF genes lead to retinitis pigmentosa, a hereditary disease restricted to the eye. Using cells from patients with 10 different mutations, we show that all clinically relevant RP-PRPF defects affect the stoichiometry of spliceosomal small nuclear RNAs (snRNAs), the protein composition of tri-small nuclear ribonucleoproteins and the kinetics of spliceosome assembly. These mutations cause inefficient splicing in vitro and affect constitutive splicing ex-vivo by impairing the removal of at least 9% of endogenously expressed introns. Alternative splicing choices are also affected when RP-PRPF defects are present. Furthermore, we show that the steady-state levels of snRNAs and processed pre-mRNAs are highest in the retina, indicating a particularly elevated splicing activity. Our results suggest a role for PRPFs defects in the etiology of PRPF-linked retinitis pigmentosa, which appears to be a truly systemic splicing disease. Although these mutations cause widespread and important splicing defects, they are likely tolerated by the majority of human tissues but are critical for retinal cell survival.
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http://dx.doi.org/10.1093/hmg/ddr094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090192PMC
June 2011

Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa.

J Med Genet 2010 Jul 27;47(7):499-506. Epub 2010 May 27.

Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA.

Background: Usher syndrome type II (USH2) is an autosomal recessive disorder characterised by retinitis pigmentosa (RP) and mild to moderate sensorineural hearing loss. Mutations in the USH2A gene are the most common cause of USH2 and are also a cause of some forms of RP without hearing loss (ie, non-syndromic RP). The USH2A gene was initially identified as a transcript comprised of 21 exons but subsequently a longer isoform containing 72 exons was identified.

Methods: The 51 exons unique to the long isoform of USH2A were screened for mutations among a core set of 108 patients diagnosed with USH2 and 80 patients with non-syndromic RP who were all included in a previously reported screen of the short isoform of USH2A. For several exons, additional patients were screened.

Results: In total, 35 deleterious mutations were identified including 17 nonsense mutations, 9 frameshift mutations, 5 splice-site mutations, and 4 small in-frame deletions or insertions. Twenty-seven mutations were novel. In addition, 65 rare missense changes were identified. A method of classifying the deleterious effect of the missense changes was developed using the summed results of four different mutation assessment algorithms, SIFT, pMUT, PolyPhen, and AGVGD. This system classified 8 of the 65 changes as 'likely deleterious' and 9 as 'possibly deleterious'.

Conclusion: At least one mutation was identified in 57-63% of USH2 cases and 19-23% of cases of non-syndromic recessive RP (calculated without and including probable/possible deleterious changes) thus supporting that USH2A is the most common known cause of RP in the USA.
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http://dx.doi.org/10.1136/jmg.2009.075143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070405PMC
July 2010

Extended wearing trial of Trifield lens device for 'tunnel vision'.

Ophthalmic Physiol Opt 2010 May;30(3):240-52

Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114-2500, USA.

Severe visual field constriction (tunnel vision) impairs the ability to navigate and walk safely. We evaluated Trifield glasses as a mobility rehabilitation device for tunnel vision in an extended wearing trial. Twelve patients with tunnel vision (5-22 degrees wide) due to retinitis pigmentosa or choroideremia participated in the 5-visit wearing trial. To expand the horizontal visual field, one spectacle lens was fitted with two apex-to-apex prisms that vertically bisected the pupil on primary gaze. This provides visual field expansion at the expense of visual confusion (two objects with the same visual direction). Patients were asked to wear these spectacles as much as possible for the duration of the wearing trial (median 8, range 6-60 weeks). Clinical success (continued wear, indicating perceived overall benefit), visual field expansion, perceived direction and perceived visual ability were measured. Of 12 patients, nine chose to continue wearing the Trifield glasses at the end of the wearing trial. Of those nine patients, at long-term follow-up (35-78 weeks), three reported still wearing the Trifield glasses. Visual field expansion (median 18, range 9-38 degrees) was demonstrated for all patients. No patient demonstrated adaptation to the change in visual direction produced by the Trifield glasses (prisms). For reported difficulty with obstacles, some differences between successful and non-successful wearers were found. Trifield glasses provided reported benefits in obstacle avoidance to 7 of the 12 patients completing the wearing trial. Crowded environments were particularly difficult for most wearers. Possible reasons for long-term discontinuation and lack of adaptation to perceived direction are discussed.
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http://dx.doi.org/10.1111/j.1475-1313.2010.00718.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867070PMC
May 2010

Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A.

Arch Ophthalmol 2010 Apr;128(4):403-11

Berman-Gund Laboratory for Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

Objective: To determine whether lutein supplementation will slow visual function decline in patients with retinitis pigmentosa receiving vitamin A.

Design: Randomized, controlled, double-masked trial of 225 nonsmoking patients, aged 18 to 60 years, evaluated over a 4-year interval. Patients received 12 mg of lutein or a control tablet daily. All were given 15,000 IU/d of vitamin A palmitate. Randomization took into account genetic type and baseline serum lutein level.

Main Outcome Measures: The primary outcome was the total point score for the Humphrey Field Analyzer (HFA) 30-2 program; prespecified secondary outcomes were the total point scores for the 60-4 program and for the 30-2 and 60-4 programs combined, 30-Hz electroretinogram amplitude, and Early Treatment Diabetic Retinopathy Study acuity.

Results: No significant difference in rate of decline was found between the lutein plus vitamin A and control plus vitamin A groups over a 4-year interval for the HFA 30-2 program. For the HFA 60-4 program, a decrease in mean rate of sensitivity loss was observed in the lutein plus vitamin A group (P = .05). Mean decline with the 60-4 program was slower among those with the highest serum lutein level or with the highest increase in macular pigment optical density at follow-up (P = .01 and P = .006, respectively). Those with the highest increase in macular pigment optical density also had the slowest decline in HFA 30-2 and 60-4 combined field sensitivity (P = .005). No significant toxic effects of lutein supplementation were observed.

Conclusion: Lutein supplementation of 12 mg/d slowed loss of midperipheral visual field on average among nonsmoking adults with retinitis pigmentosa taking vitamin A. Application to Clinical Practice Data are presented that support use of 12 mg/d of lutein to slow visual field loss among nonsmoking adults with retinitis pigmentosa taking vitamin A.

Trial Registration: ClinicalTrials.gov Identifier: NCT00346333.
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http://dx.doi.org/10.1001/archophthalmol.2010.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987594PMC
April 2010

Replacement gene therapy with a human RPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosis.

Hum Gene Ther 2010 Aug;21(8):993-1004

Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, and Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

RPGR-interacting protein-1 (RPGRIP1) is localized in the photoreceptor-connecting cilium, where it anchors the RPGR (retinitis pigmentosa GTPase regulator) protein, and its function is essential for photoreceptor maintenance. Genetic defect in RPGRIP1 is a known cause of Leber congenital amaurosis (LCA), a severe, early-onset form of retinal degeneration. We evaluated the efficacy of replacement gene therapy in a murine model of LCA carrying a targeted disruption of RPGRIP1. The replacement construct, packaged in an adeno-associated virus serotype 8 (AAV8) vector, used a rhodopsin kinase gene promoter to drive RPGRIP1 expression. Both promoter and transgene were of human origin. After subretinal delivery of the replacement gene in the mutant mice, human RPGRIP1 was expressed specifically in photoreceptors, localized correctly in the connecting cilia, and restored the normal localization of RPGR. Electroretinogram and histological examinations showed better preservation of rod and cone photoreceptor function and improved photoreceptor survival in the treated eyes. This study demonstrates the efficacy of human gene replacement therapy and validates a gene therapy design for future clinical trials in patients afflicted with this condition. Our results also have therapeutic implications for other forms of retinal degenerations attributable to a ciliary defect.
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http://dx.doi.org/10.1089/hum.2009.218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928706PMC
August 2010

The relationship of macular pigment optical density to serum lutein in retinitis pigmentosa.

Invest Ophthalmol Vis Sci 2010 Feb 24;51(2):1086-91. Epub 2009 Sep 24.

The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA.

Purpose: To determine whether macular pigment optical density (MPOD) is related to serum lutein or serum zeaxanthin in patients with retinitis pigmentosa.

Methods: The authors measured MPOD with heterochromatic flicker photometry, serum lutein and serum zeaxanthin by high performance liquid chromatography, and central foveal retinal thickness by optical coherence tomography (OCT) in 176 patients (age range, 18-68 years) with typical forms of retinitis pigmentosa; 37 (21%) of these patients had cystoid macular edema (CME) by OCT. The authors performed multiple regression analysis with MPOD as the dependent variable and with log(e) serum lutein and log(e) serum zeaxanthin as independent variables adjusting for age, sex, iris color, central foveal retinal thickness, and, in some analyses, serum total cholesterol.

Results: MPOD increased with increasing serum lutein (P = 0.0017) and decreased with increasing serum total cholesterol (P = 0.0025) but was unrelated to serum zeaxanthin. MPOD was higher in patients with brown irides than in patients with lighter irides (P = 0.014) and was nonmonotonically related to central foveal retinal thickness (P < 0.0001), being lower in eyes with more photoreceptor cell loss and in eyes with moderate to marked CME.

Conclusions: MPOD is independently related to serum lutein, serum total cholesterol, iris color, and central foveal retinal thickness in patients with retinitis pigmentosa.
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http://dx.doi.org/10.1167/iovs.09-3396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849289PMC
February 2010

A single-base substitution within an intronic repetitive element causes dominant retinitis pigmentosa with reduced penetrance.

Hum Mutat 2009 Sep;30(9):1340-7

Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

We report the study of a large American family displaying autosomal dominant retinitis pigmentosa with reduced penetrance, a form of hereditary retinal degeneration. Although the inheritance pattern and previous linkage mapping pointed to the involvement of the PRPF31 gene, extensive screening of all its exons and their boundaries failed in the past to reveal any mutation. In this work, we sequenced the entire PRPF31 genomic region by both the classical Sanger method and ultrahigh throughput (UHT) sequencing. Among the many variants identified, a single-base substitution (c.1374+654C>G) located deep within intron 13 and inside a repetitive DNA element was common to all patients and obligate asymptomatic carriers. This change created a new splice donor site leading to the synthesis of two mutant PRPF31 isoforms, degraded by nonsense-mediated mRNA decay. As a consequence, amounts of PRPF31 mRNA derived from the mutant allele were very reduced, with no evidence of mutant proteins being synthesized. Our results indicate that c.1374+654C>G causes retinitis pigmentosa via haploinsufficiency, similar to the vast majority of PRPF31 mutations described so far. We discuss the potential of UHT sequencing technologies in mutation screening and the continued identification of pathogenic splicing mutations buried deep within intronic regions.
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http://dx.doi.org/10.1002/humu.21071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753193PMC
September 2009

Search for a correlation between telomere length and severity of retinitis pigmentosa due to the dominant rhodopsin Pro23His mutation.

Mol Vis 2009 27;15:592-7. Epub 2009 Mar 27.

Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.

Purpose: Great variation exists in the age of onset of symptoms and the severity of disease at a given age in patients with retinitis pigmentosa (RP). The final pathway for this disease may involve apoptotic photoreceptor cell death. Telomere length is associated with biologic aging, senescence, and apoptosis. We evaluated whether the length of telomeres in leukocytes correlated with the severity of RP in patients with the Pro23His rhodopsin mutation who have shown marked heterogeneity in disease severity.

Methods: We evaluated 122 patients with the Pro23His rhodopsin mutation. The patients' retinal function was stratified according to their 30-Hz cone electroretinogram (ERG). The length of telomeres in leukocytes was measured by the quantitative real time polymerase chain reaction (qRT-PCR) method in the 15 patients with the highest age-adjusted 30-Hz ERG amplitudes and in the 15 patients with the lowest amplitudes.

Results: Mean leukocyte telomere length was similar in the 15 patients with the highest cone ERG amplitudes (median: 0.40 units; interquartile range 0.36-0.56) and the 15 patients with the lowest cone amplitudes (median: 0.41 units; inter quartile range 0.34 -0.64; p=0.95).

Conclusions: We found no evidence for an association between telomere length and the severity of RP as monitored by the cone ERG in patients with the Pro23His rhodopsin mutation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661004PMC
April 2009

A homozygous missense mutation in the IRBP gene (RBP3) associated with autosomal recessive retinitis pigmentosa.

Invest Ophthalmol Vis Sci 2009 Apr 13;50(4):1864-72. Epub 2008 Dec 13.

Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Massachusetts 02114, USA.

Purpose: Interphotoreceptor retinoid-binding protein (IRBP) has been considered essential for normal rod and cone function, as it mediates the transport of retinoids between the photoreceptors and the retinal pigment epithelium. This study was performed to determine whether mutations in the IRBP gene (RBP3) are associated with photoreceptor degeneration.

Methods: A consanguineous family was ascertained in which four children had autosomal recessive retinitis pigmentosa (RP). Homozygosity mapping performed with SNP microarrays revealed only one homozygous region shared by all four affected siblings. Sequencing of RBP3, contained in this region, was performed in this family and others with recessive RP. Screening was also performed on patients with various other forms of retinal degeneration or malfunction.

Results: Sequence analysis of RBP3 revealed a homozygous missense mutation (p.Asp1080Asn) in the four affected siblings. The mutation affects a residue that is completely conserved in all four homologous modules of the IRBP protein of vertebrate species and in C-terminal-processing proteases, photosynthesis enzymes found in bacteria, algae, and plants. Based on the previously reported crystal structure of Xenopus IRBP, the authors predict that the Asp1080-mediated conserved salt bridge that appears to participate in scaffolding of the retinol-binding domain is abolished by the mutation. No RBP3 mutations were detected in 395 unrelated patients with recessive or isolate RP or in 680 patients with other forms of hereditary retinal degeneration.

Conclusions: Mutations in RBP3 are an infrequent cause of autosomal recessive RP. The mutation Asp1080Asn may alter the conformation of the IRBP protein by disrupting a conserved salt bridge.
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http://dx.doi.org/10.1167/iovs.08-2497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823395PMC
April 2009