Mullins Lab Publications

Subscribe to Mullins Lab Publications feed Mullins Lab Publications
Updated: 4 days 13 hours ago

The ARMS2 A69S Polymorphism Is Associated with Delayed Rod-Mediated Dark Adaptation in Eyes at Risk for Incident Age-Related Macular Degeneration.

Mon, 2020-01-06 20:09
Related Articles

The ARMS2 A69S Polymorphism Is Associated with Delayed Rod-Mediated Dark Adaptation in Eyes at Risk for Incident Age-Related Macular Degeneration.

Ophthalmology. 2019 04;126(4):591-600

Authors: Mullins RF, McGwin G, Searcey K, Clark ME, Kennedy EL, Curcio CA, Stone EM, Owsley C

Abstract
PURPOSE: To examine the association between sequence variants in genetic risk factors for age-related macular degeneration (AMD) and delayed rod-mediated dark adaptation (RMDA), the first functional biomarker for incident AMD, in older adults with normal macular health and early AMD.
DESIGN: Cross-sectional.
PARTICIPANTS: Adults 60 years of age or older showing normal macular health (defined as both eyes at step 1 on the Age-Related Eye Disease Study 9-step AMD classification system) and those with AMD in one or both eyes (defined as steps 2-9).
METHODS: Single nucleotide polymorphisms were genotyped in the complement factor H (CFH) and ARMS2 genes using a Taqman assay. Rod-mediated dark adaptation was assessed in 1 eye after photobleach with targets centered at 5° on the inferior vertical meridian. Rate of dark adaptation was defined by rod intercept time (RIT), duration (in minutes) required for sensitivity to reach a criterion sensitivity level in the latter half of the second component of rod recovery. Associations between CFH and ARMS2 polymorphisms and RMDA were adjusted for age and smoking.
MAIN OUTCOME MEASURE: Rod intercept time.
RESULTS: The sample consisted of 543 participants having both genotype and RIT determination; 408 showed normal macular health and 135 demonstrated AMD, most having early AMD (124 of 135). For the combined sample, higher RIT (slower RMDA) was observed for both the A69S variant in ARMS2 and the Y402H variant in CFH (adjusted P = 0.0001 and P = 0.0023, respectively). For healthy participants, the A69S variant in ARMS2 was associated with higher RIT (adjusted P = 0.0011), whereas the Y402H variant in CFH was not (adjusted P = 0.2175). For AMD patients, the A69S variant of ARMS2 and the Y402H variant of CFH were associated with higher RIT (adjusted P = 0.0182 and P = 0.0222, respectively). Those with a larger number of high-risk ARMS2 and CFH alleles showed higher RIT, in both healthy and AMD groups (adjusted P = 0.0002 and P < 0.0001, respectively).
CONCLUSIONS: We report a novel association wherein older adults with high-risk ARMS2 and CFH genotypes are more likely to demonstrate delayed RMDA, the first functional biomarker for incident early AMD. Before the AMD clinical phenotype is present, those showing normal macular health with the ARMS2 A69S allele demonstrate delayed RMDA. Understanding ARMS2 function is a research priority.

PMID: 30389424 [PubMed - indexed for MEDLINE]

Wide-Field Swept-Source OCT and Angiography in X-Linked Retinoschisis.

Mon, 2019-12-23 18:06
Related Articles

Wide-Field Swept-Source OCT and Angiography in X-Linked Retinoschisis.

Ophthalmol Retina. 2019 02;3(2):178-185

Authors: Han IC, Whitmore SS, Critser DB, Lee SY, DeLuca AP, Daggett HT, Affatigato LM, Mullins RF, Tucker BA, Drack AV, Stone EM

Abstract
PURPOSE: Retinal vascular and structural changes, particularly outside of the central macula, are not well characterized in X-linked retinoschisis (XLRS). We aim to describe wide-field swept-source OCT (SS-OCT) and swept-source OCT angiography (SS-OCTA) findings in XLRS.
DESIGN: Retrospective, cross-sectional study at a tertiary referral center.
PARTICIPANTS: Nine consecutive male patients with molecularly confirmed XLRS.
METHODS: All patients underwent complete ophthalmic examination with multimodal imaging, including SS-OCT with SS-OCTA (PLEX Elite 9000; Carl-Zeiss Meditec Inc., Dublin, CA). Images were then reviewed by 2 retinal specialists as independent graders to determine the frequency and distribution of retinal structural and vascular abnormalities.
MAIN OUTCOME MEASURES: Structural and vascular abnormalities seen on SS-OCT and SS-OCTA in patients with XLRS, with attention to the retinal layers involved, the regional distribution of schitic spaces in the posterior pole, and vascular abnormalities within the superficial and deep capillary plexuses.
RESULTS: Eighteen eyes from 9 male patients (mean age, 20 years; range 9-40) with molecularly confirmed XLRS were included. Median best-corrected visual acuity measured 20/63 (range, 20/25-10/300). A total of 17 of 18 eyes (94.4%) were noted to have schitic spaces on SS-OCT, and these were observed to be predominantly within the inner nuclear layer in all 17 eyes. A regional variation in the distribution of cysts was noted, with schitic spaces within the ganglion cell layer (13/17 eyes; 76.5%) observed to be perifoveal and those within the outer nuclear layer (8/17 eyes, 47.1%) observed to be mostly extramacular. All eyes had vascular abnormalities on SS-OCTA, including an irregular foveal avascular zone and flow loss within the deep capillary plexus corresponding to the distribution of the schisis.
CONCLUSIONS: Wide-field SS-OCT and SS-OCTA provide detailed visualization of structural and vascular changes in XLRS and may be helpful for monitoring disease progression or treatment response in clinical trials for the disease.

PMID: 31014769 [PubMed - indexed for MEDLINE]

Subretinal pseudocysts: A novel OCT finding in diabetic macular edema.

Mon, 2019-12-09 14:27
Related Articles

Subretinal pseudocysts: A novel OCT finding in diabetic macular edema.

Am J Ophthalmol Case Rep. 2019 Dec;16:100567

Authors: Sacconi R, Lutty GA, Mullins RF, Borrelli E, Bandello F, Querques G

Abstract
Purpose: to report the presence of a new structural optical coherence tomography (OCT) finding, namely subretinal pseudocysts, in a patient affected by diabetic retinopathy (DR).
Observations: A 52-year-old man affected by type 2 diabetes from 10 years was referred to our department complaining of a visual decline in both eyes. Best corrected visual acuity was 20/100 and 20/80 in the right and left eye, respectively. Fundus examination, fluorescein angiography, and structural OCT revealed the presence of a proliferative DR with diabetic macular edema in both eyes. Interestingly, structural OCT showed subretinal pseudocystic spaces inside the subretinal fluid of the macular neuroretinal detachment.
Conclusions and importance: Subretinal pseudocysts are a new structural OCT entity. We reported for the first time the evidence that pseudocysts may develop in the subretinal space in a case of diabetic macular edema.

PMID: 31788575 [PubMed]

AUTOIMMUNE RETINOPATHY MIMICKING HERITABLE RETINAL DEGENERATION IN A PATIENT WITH COMMON VARIABLE IMMUNE DEFICIENCY.

Mon, 2019-12-02 11:39
Related Articles

AUTOIMMUNE RETINOPATHY MIMICKING HERITABLE RETINAL DEGENERATION IN A PATIENT WITH COMMON VARIABLE IMMUNE DEFICIENCY.

Retin Cases Brief Rep. 2019 Nov 21;:

Authors: Wiley LA, Binkley EM, DeLuca AP, Workalemahu G, Tatro NJ, Luse MA, Kennedy EL, Folk JC, Scheetz TE, Ballas ZK, Tucker BA, Mullins RF, Han IC, Stone EM

Abstract
PURPOSE: 1) To describe a case of autoimmune retinopathy mimicking heritable photoreceptor degeneration in a patient with common variable immune deficiency and 2) to investigate the humoral and cell-mediated branches of the immune system in this patient to better understand the mechanism of immune-mediated photoreceptor damage in this disease.
METHODS: Retrospective chart review with evaluation of multimodal imaging, genotype analysis, and investigation of circulating autoantibodies and T-cell response to retinal antigens.
RESULTS: A 40-year-old woman with bilateral, progressive vision loss was referred for evaluation of a possible inherited retinal degeneration. She was found to have asymmetric peripheral visual field constriction, cystoid macular edema, vitreous cells, and bone spicule-like pigmentary changes in both eyes. An extensive workup for underlying infectious or inflammatory causes was unrevealing, and molecular analysis for heritable retinal degeneration failed to identify a plausible disease-causing genotype. Screening for antiretinal antibodies showed the presence of multiple antiretinal antibodies, consistent with a diagnosis of autoimmune retinopathy. Immunologic workup demonstrated markedly decreased levels of serum IgA and IgG, consistent with common variable immune deficiency. T-cells isolated from the patient showed increased proliferation when stimulated with human retinal proteins, supporting a role for both cell- and humoral-mediated autoimmunity. Treatment with mycophenolate mofetil and intravenous immunoglobin therapy slowed the progression of disease and resulted in preservation of her central vision.
CONCLUSION: Autoimmune retinopathy can be seen in common variable immune deficiency and has clinical findings similar to heritable photoreceptor degeneration. Both the humoral and cellular immune responses are involved in the pathophysiology. Immune modulatory therapy has stabilized the disease course in this patient and may play an important role in the management of autoimmune retinopathy.

PMID: 31764884 [PubMed - as supplied by publisher]

Single-cell transcriptomics of the human retinal pigment epithelium and choroid in health and macular degeneration.

Mon, 2019-11-18 09:41
Related Articles

Single-cell transcriptomics of the human retinal pigment epithelium and choroid in health and macular degeneration.

Proc Natl Acad Sci U S A. 2019 Nov 11;:

Authors: Voigt AP, Mulfaul K, Mullin NK, Flamme-Wiese MJ, Giacalone JC, Stone EM, Tucker BA, Scheetz TE, Mullins RF

Abstract
The human retinal pigment epithelium (RPE) and choroid are complex tissues that provide crucial support to the retina. Disease affecting either of these supportive tissues can lead to irreversible blindness in the setting of age-related macular degeneration. In this study, single-cell RNA sequencing was performed on macular and peripheral regions of RPE-choroid from 7 human donor eyes in 2 independent experiments. In the first experiment, total RPE/choroid preparations were evaluated and expression profiles specific to RPE and major choroidal cell populations were identified. As choroidal endothelial cells represent a minority of the total RPE/choroidal cell population but are strongly implicated in age-related macular degeneration (AMD) pathogenesis, a second single-cell RNA-sequencing experiment was performed using endothelial cells enriched by magnetic separation. In this second study, we identified gene expression signatures along the choroidal vascular tree, classifying the transcriptome of human choriocapillaris, arterial, and venous endothelial cells. We found that the choriocapillaris highly and specifically expresses the regulator of cell cycle gene (RGCC), a gene that responds to complement activation and induces apoptosis in endothelial cells. In addition, RGCC was the most up-regulated choriocapillaris gene in a donor diagnosed with AMD. These results provide a characterization of the human RPE and choriocapillaris transcriptome, offering potential insight into the mechanisms of choriocapillaris response to complement injury and choroidal vascular disease in age-related macular degeneration.

PMID: 31712411 [PubMed - as supplied by publisher]

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Mon, 2019-11-11 07:02
Related Articles

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

JAMA. 2019 11 05;322(17):1682-1691

Authors: Genetics of Glaucoma in People of African Descent (GGLAD) Consortium, Hauser MA, Allingham RR, Aung T, Van Der Heide CJ, Taylor KD, Rotter JI, Wang SJ, Bonnemaijer PWM, Williams SE, Abdullahi SM, Abu-Amero KK, Anderson MG, Akafo S, Alhassan MB, Asimadu I, Ayyagari R, Bakayoko S, Nyamsi PB, Bowden DW, Bromley WC, Budenz DL, Carmichael TR, Challa P, Chen YI, Chuka-Okosa CM, Cooke Bailey JN, Costa VP, Cruz DA, DuBiner H, Ervin JF, Feldman RM, Flamme-Wiese M, Gaasterland DE, Garnai SJ, Girkin CA, Guirou N, Guo X, Haines JL, Hammond CJ, Herndon L, Hoffmann TJ, Hulette CM, Hydara A, Igo RP, Jorgenson E, Kabwe J, Kilangalanga NJ, Kizor-Akaraiwe N, Kuchtey RW, Lamari H, Li Z, Liebmann JM, Liu Y, Loos RJF, Melo MB, Moroi SE, Msosa JM, Mullins RF, Nadkarni G, Napo A, Ng MCY, Nunes HF, Obeng-Nyarkoh E, Okeke A, Okeke S, Olaniyi O, Olawoye O, Oliveira MB, Pasquale LR, Perez-Grossmann RA, Pericak-Vance MA, Qin X, Ramsay M, Resnikoff S, Richards JE, Schimiti RB, Sim KS, Sponsel WE, Svidnicki PV, Thiadens AAHJ, Uche NJ, van Duijn CM, de Vasconcellos JPC, Wiggs JL, Zangwill LM, Risch N, Milea D, Ashaye A, Klaver CCW, Weinreb RN, Ashley Koch AE, Fingert JH, Khor CC

Abstract
Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.
Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.
Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.
Exposures: Genetic variants associated with primary open-angle glaucoma.
Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data.
Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.
Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

PMID: 31688885 [PubMed - in process]

Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury.

Mon, 2019-11-04 05:34
Related Articles

Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury.

Sci Rep. 2018 09 06;8(1):13387

Authors: Zeng S, Wen KK, Workalemahu G, Sohn EH, Wu M, Chirco KR, Flamme-Wiese MJ, Liu X, Stone EM, Tucker BA, Mullins RF

Abstract
Age-related macular degeneration (AMD) is a common, blinding disease associated with increased complement system activity. Eyes with AMD show elevated accumulation of the membrane attack complex (MAC) in the choriocapillaris and degeneration of macular choriocapillaris endothelial cells (ECs). Thus, one could reasonably conclude that the endothelial cell death that occurs in AMD is due to injury by the MAC. We therefore sought to identify strategies for protecting ECs against MAC lysis. RF/6A endothelial cells were pre-incubated with a library of FDA-approved small molecules, followed by incubation with complement intact human serum quantification of cell death. Two closely related molecules identified in the screen, econazole nitrate and miconazole nitrate, were followed in validation and mechanistic studies. Both compounds reduced lysis of choroidal ECs treated with complement-intact serum, across a range of doses from 1 to 100 µM. Cell rescue was confirmed in mouse primary choroidal ECs. Both exosome release and cell surface roughness (assessed using a Holomonitor system) were reduced by drug pretreatment in RF/6A cells, whereas endosome formation increased with both drugs, consistent with imidazole-mediated alterations of cell surface dynamics. The results in the current study provide further proof of principle that small molecules can protect choroidal ECs from MAC-induced cell death and suggest that FDA approved compounds may be beneficial in reducing vascular loss and progression of AMD.

PMID: 30190604 [PubMed - indexed for MEDLINE]