Abstract

PIEZO1 and PIEZO2 are mechanosensitive ion channels that regulate many important physiological processes including vascular blood flow, touch, and proprioception. As the eye is subject to mechanical stress and is highly perfused, these channels may play important roles in ocular function and intraocular pressure regulation. PIEZO channel expression in the eye has not been well defined, in part due to difficulties in validating available antibodies against PIEZO1 and PIEZO2 in ocular tissues. It is also unclear if PIEZO1 and PIEZO2 are differentially expressed. To address these questions, we used single-molecule fluorescence in situ hybridization (smFISH) together with transgenic reporter mice expressing PIEZO fusion proteins under the control of their endogenous promoters to compare the expression and localization of PIEZO1 and PIEZO2 in mouse ocular tissues relevant to glaucoma. We detected both PIEZO1 and PIEZO2 expression in the trabecular meshwork, ciliary body, and in the ganglion cell layer (GCL) of the retina. Piezo1 mRNA was more abundantly expressed than Piezo2 mRNA in these ocular tissues. Piezo1 but not Piezo2 mRNA was detected in the inner nuclear layer and outer nuclear layer of the retina. Our results suggest that PIEZO1 and PIEZO2 are differentially expressed and may have distinct roles as mechanosensors in glaucoma-relevant ocular tissues.

View details for DOI 10.1016/j.exer.2023.109675

View details for PubMedID 37820892

Abstract

Although glaucoma is a disease modulated by eye pressure, the mechanisms of pressure sensing in the eye are not well understood. Here, we investigated associations between mechanosensitive ion channel gene variants and primary open-angle glaucoma (POAG). Common (minor allele frequency > 5%) single nucleotide polymorphisms located within the genomic regions of 20 mechanosensitive ion channel genes in the K2P, TMEM63, PIEZO and TRP channel families were assessed using genotype data from the NEIGHBORHOOD consortium of 3853 cases and 33,480 controls. Rare (minor allele frequency < 1%) coding variants were assessed using exome array genotyping data for 2606 cases and 2606 controls. Association with POAG was analyzed using logistic regression adjusting for age and sex. Two rare PIEZO1 coding variants with protective effects were identified in the NEIGHBOR dataset: R1527H, (OR 0.17, P = 0.0018) and a variant that alters a canonical splice donor site, g.16-88737727-C-G Hg38 (OR 0.38, P = 0.02). Both variants showed similar effects in the UK Biobank and the R1527H also in the FinnGen database. Several common variants also reached study-specific thresholds for association in the NEIGHBORHOOD dataset. These results identify novel variants in several mechanosensitive channel genes that show associations with POAG, suggesting that these channels may be potential therapeutic targets.

View details for DOI 10.1038/s41598-023-43072-3

View details for PubMedID 37741866

View details for PubMedCentralID PMC10517927

Abstract

A 62-year-old woman with mild myopia presented to her local optometrist for a routine examination and was found to have intraocular pressure (IOP) of 30 mm Hg in both eyes and cupped nerves. She had a family history of glaucoma in her father. She was started on latanoprost in both eyes and was referred for a glaucoma evaluation. On initial evaluation, her IOP was 25 mm Hg in the right eye and 26 mm Hg in the left eye. Central corneal thickness measured 592 µm in the right eye and 581 µm in the left eye. Her angles were open to gonioscopy without any peripheral anterior synechia. She had 1+ nuclear sclerosis with a corrected distance visual acuity (CDVA) of 20/25 in the right eye and 20/30- in the left eye and uncorrected near visual acuity of J1+ in each eye. Her nerves were 0.85 mm in the right eye and 0.75 mm in the left eye. Optical coherence tomography (OCT) showed retinal nerve fiber layer thinning and a dense superior arcuate scotoma into fixation in her right eye, and superior and inferior arcuate scotomas in her left eye (Figures 1 and 2JOURNAL/jcrs/04.03/02158034-202307000-00019/figure1/v/2023-06-26T195222Z/r/image-tiffJOURNAL/jcrs/04.03/02158034-202307000-00019/figure2/v/2023-06-26T195222Z/r/image-tiff, Supplemental Figures 1 and 2, available at http://links.lww.com/JRS/A882 and http://links.lww.com/JRS/A883). She was successively trialed on fixed combination brimonidine-timolol, dorzolamide, and netarsudil, in addition to her latanoprost, but her IOP remained in the mid- to upper 20s in both eyes. The addition of acetazolamide lowered the pressure to 19 mm Hg in both eyes, but she tolerated it poorly. Methazolamide was also attempted with similar side effects. We elected to perform left eye cataract surgery combined with 360-degree viscocanaloplasty and insertion of a Hydrus microstent (Alcon Laboratories, Inc.). Surgery was uncomplicated with IOP of 16 mm Hg on postoperative day 1 with no glaucoma medications. However, by postoperative week 3, IOP returned to 27 mm Hg, and despite restarting latanoprost-netarsudil and finishing her steroid taper, IOP remained at 27 mm Hg by postoperative week 6. Brimonidine-timolol was added back to her left eye regimen and at postoperative week 8, IOP had elevated to 45 mm Hg. Maximizing her therapy with the addition of topical dorzolamide and oral methazolamide brought her IOP back down to 30 mm Hg. At that point, the decision was made to proceed with trabeculectomy of the left eye. The trabeculectomy was uneventful. However, postoperative attempts to augment filtration were rendered less successful by extremely thick Tenon layer. At her most recent follow-up the pressure in the left eye was mid-teens with brimonidine-timolol and dorzolamide. Her right eye IOP is in the upper 20s on maximum topical therapy. Knowing her postoperative course in the left eye, how would you manage the right eye? In addition to currently available options, would you consider a supraciliary shunt such as the MINIject (iSTAR) if such a device were U.S. Food and Drug Administration (FDA)-approved?

View details for DOI 10.1097/j.jcrs.0000000000001221

View details for PubMedID 37390324

Abstract

To investigate an association between stereoacuity and the presence of central visual field defects (CVFDs) due to glaucoma.Prospective, cross-sectional cohort study.Participants with early to moderate glaucoma with visual acuity better than 20/40, less than 2-line difference in visual acuity between eyes, and 2 reliable Humphrey VFs (24-2 SITA standard) with mean deviation (MD) in the worse eye better than -12dB.Stereoacuity was measured using the Titmus stereo test. Participants with a significant field defect (P<0.5%) in any one of the central four points in the 24-2 SITA standard total deviation map in either eye were classified as having a CVFD. Vision-related quality of life (VR-QOL) was measured by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) scores. Logistic regression was used to determine the association between level of stereoacuity and age, gender, race, glaucoma type, presence of CVFDs, visual acuity, contrast sensitivity, and visual field MD.Stereoacuity in the CVFD and no CVFD groups.Sixty-five participants met the inclusion criteria. The mean age was 64.3 ± 8.0 years and 64.6% were women. Median stereoacuity was 60 arc sec (inter-quartile range 40-120). Forty-two (65%) patients had CVFDs and 23 (35%) patients did not. Median stereoacuity for the CVFD group was worse than the non-CVFD group (60 arc sec (IQR 50-140) vs. 40 arc sec (IQR 40-80); p=0.001), respectively. The non-CVFD group had a higher percentage of participants with normal stereopsis compared to the non-CVFD group (61% vs 21%, p=0.001). Multivariable analysis found that the presence of CVFDs was associated with worse stereopsis level (odds ratio 4.49, p=0.021). The CVFD group had a lower VFQ-25 composite score (84.0 vs 91.4, p=0.004), and lower VFQ-25 sub-scale scores for general vision, near activities, and mental health (P<0.05).CVFDs were associated with increased odds of poor stereoacuity in patients with early to moderate glaucomatous VF loss. Specifically, patients without CVFDs are more likely to have normal stereopsis and higher VR-QOL than those with CVFDs. Patients with CVFDs should be counseled regarding how depth perception difficulties may affect daily living.

View details for DOI 10.1016/j.ogla.2023.04.003

View details for PubMedID 37080537

Abstract

To provide 4-year data on the efficacy and safety of gonioscopy-assisted transluminal trabeculotomy (GATT) in patients with open-angle glaucoma.Retrospective case series.Eyes of patients >18 years of age who underwent GATT by a single surgeon at Wills Eye Hospital with at least 36 months follow-up.Postoperative changes in outcome measures including intraocular pressure (IOP), medication use and visual acuity were recorded. Failure was defined as IOP > 21mmHg or less than 20% reduction below baseline at any postoperative visit after three months, or need for further glaucoma surgery.Main outcome measures were failure rate, IOP, number of glaucoma medications, and visual acuity at 4 years.59 patients (74 eyes), age 57.1±18.5 years (37.8% female) underwent the GATT procedure. Average follow-up was 47.0±6.7 months (range 35.6 to 76.5 months). Mean IOP was 27.0±10.0 mmHg preoperatively and 14.8±6.5 mmHg at 4 years (45% IOP decrease; P<0.01). Mean number of medications decreased from 3.2±1.0 preoperatively to 2.3±1.0 at 4 years (P< 0.01). The cumulative failure rate at 4 years was 53.9%, and the cumulative reoperation rate was 42.0%. No significant differences between patients with primary open-angle glaucoma and other types of glaucoma were found.GATT can be a safe and effective conjunctival-sparing surgery for in treating various forms of open-angle glaucoma at 4 years.

View details for DOI 10.1016/j.ogla.2023.01.005

View details for PubMedID 36702382

View details for DOI 10.1172/JCI173784

View details for PubMedID 37526085

Abstract

Normal-tension glaucoma is a form of optic nerve degeneration that is characterized by loss of retinal ganglion cells independent of eye pressure elevation. In this issue of the JCI, Pan et al. report the discovery in a Japanese family of a mutation in the METTL23 gene, which encodes a DNA methyltransferase that causes normal-pressure glaucoma in haploinsufficiency. Inherited as an autosomal dominant condition, METTL23 deficiency revealed an important function in the regulation of pS2 and the downstream NF-kappaB signaling pathway, which has previously been linked to glaucomatous optic nerve degeneration. These findings are the first direct link between defective epigenetic regulatory machinery and genetic forms of optic nerve degeneration.

View details for DOI 10.1172/JCI163670

View details for PubMedID 36317630

View details for Web of Science ID 000844401302301