Investigation of the functional impact of CHED- and FECD4-associated SLC4A11 mutations in human corneal endothelial cells.

Mutations in the solute linked carrier family 4 member 11 (SLC4A11) gene are associated with congenital hereditary endothelial dystrophy (CHED) and Fuchs corneal endothelial dystrophy type 4 (FECD4), both characterized by corneal endothelial cell (CEnC) dysfunction and/or cell loss leading to corneal edema and visual impairment. In this study, we characterize the impact of CHED-/FECD4-associated SLC4A11 mutations on CEnC function and SLC4A11 protein localization by generating and comparing human CEnC (hCEnC) lines expressing wild type SLC4A11 (SLC4A11WT) or mutant SLC4A11 harboring CHED-/FECD4-associated SLC4A11 mutations (SLC4A11MU). SLC4A11WT and SLC4A11MU hCEnC lines were generated to express either SLC4A11 variant 2 (V2WT and V2MU) or variant 3 (V3WT and V3MU), the two major variants expressed in ex vivo hCEnC. Functional assays were performed to assess cell barrier, proliferation, viability, migration, and NH3-induced membrane conductance. We demonstrate SLC4A11-/- and SLC4A11MU hCEnC lines exhibited increased migration rates, altered proliferation and decreased cell viability compared to SLC4A11WT hCEnC. Additionally, SLC4A11-/- hCEnC demonstrated decreased cell-substrate adhesion and membrane capacitances compared to SLC4A11WT hCEnC. Induction with 10mM NH4Cl led SLC4A11WT hCEnC to depolarize; conversely, SLC4A11-/- hCEnC hyperpolarized and the majority of SLC4A11MU hCEnC either hyperpolarized or had minimal membrane potential changes following NH4Cl induction. Immunostaining of primary hCEnC and SLC4A11WT hCEnC lines for SLC4A11 demonstrated predominately plasma membrane staining with poor or partial colocalization with mitochondrial marker COX4 within a subset of punctate subcellular structures. Overall, our findings suggest CHED-associated SLC4A11 mutations likely lead to hCEnC dysfunction, and ultimately CHED, by interfering with cell migration, proliferation, viability, membrane conductance, barrier function, and/or cell surface localization of the SLC4A11 protein in hCEnC. Additionally, based on their similar subcellular localization and exhibiting similar cell functional profiles, protein isoforms encoded by SLC4A11 variant 2 and variant 3 likely have highly overlapping functional roles in hCEnC.

Anxiety and depression in patients with uveitis: a comprehensive review of observational studies.

PURPOSE OF THE REVIEW: The purpose of this review is to provide a comprehensive summary of observational studies evaluating anxiety and depression in patients with uveitis. RECENT FINDINGS: A higher prevalence of depression was reported in patients with uveitis compared to healthy controls in most observational studies. Symptoms of anxiety were often, but not always, significantly worse in patients with uveitis compared to controls. Most studies found that patients with uveitis had reduced vision-related quality of life that was associated with anxiety and depression symptoms. SUMMARY: Patients with uveitis have a higher risk of experiencing symptoms of depression and could benefit from screening and treatment. Preliminary screening for vision-related quality of life could also help determine if the patient requires assistance in mental health or other aspects of daily living.

Confirmation of association of TGFBI p.Ser591Phe mutation with variant lattice corneal dystrophy.

PURPOSE: To provide the initial confirmation of the c.1772C>T (p.Ser591Phe) mutation in the transforming growth factor-ß-induced (TGFBI) gene as being associated with variant lattice corneal dystrophy (LCD). METHODS: Ophthalmologic examination of the proband was performed with slit lamp biomicroscopy. Saliva was collected as a source of DNA for screening all 17 exons of TGFBI, after which three family members were selectively screened for variants in exon 13. Rosetta-based structure prediction was used to calculate changes in TGFBI protein (TGFBIp) stability secondary to the c.1772C>T (p.Ser591Phe) missense mutation. RESULTS: Slit lamp examination of the 38-year-old proband revealed a clear cornea right eye and unilateral, discrete, and branching lattice lines in the anterior and mid-stroma of the central cornea left eye. Screening of TGFBI in the proband revealed a heterozygous missense mutation in exon 13 (c.1772C>T (p.Ser591Phe)) that was also identified in her affected mother but not in her brother or maternal grandmother. Calculated energy change in Rosetta (ΔΔG) for the TGFBIp variant p.Ser591Phe was 23.5, indicating a thermodynamic destabilization resulting from energetic frustration. CONCLUSIONS: The p.Ser591Phe mutation in TGFBI is associated with an unilateral variant of LCD. Rosetta-predicted stability changes indicate that the p.Ser591Phe variant is destabilizing, which is consistent with other observations for LCD-causing mutations.

Ultrawide Field Imaging of Progressive Retinal Arteriovenous Malformation in a Pediatric Patient with Wyburn-Mason Syndrome.

Wyburn-Mason syndrome (WMS) is a rare congenital disease that presents with unilateral arteriovenous malformation (AVM) in the visual pathway, midbrain, and/or skin. We report a case of a 5-year-old girl with a history of cerebral and orbital AVM who presented with left exotropia and was found to have group 3 retinal AVM consistent with WMS. Here, we use ultrawide field imaging to show the progression of retinal AVM and peripheral nonperfusion areas for a period of 1 year in a pediatric patient with WMS. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:46-48.].

Confirmation of PRDX3 c.568G>C as the Genetic Basis of Punctiform and Polychromatic Pre-Descemet Corneal Dystrophy.

PURPOSE: The aim of this study was to report the results of screening peroxiredoxin 3 (PRDX3) and PDZ domain-containing protein 8 (PDZD8) in a previously unreported pedigree with punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) to confirm that the PRDX3 mutation c.568G>C is the genetic basis of PPPCD. METHODS: Ophthalmologic examination of the proband and her affected father was performed with slit lamp biomicroscopy. Saliva was collected from the proband as a source of DNA, after which screening for PRDX3 and PDZD8 was performed. RESULTS: Slit lamp examination of the proband revealed polychromatic deposits diffusely distributed at the pre-Descemet level in both corneas and anterior subcapsular in the crystalline lens of both eyes. The proband's father also demonstrated diffuse pre-Descemetic polychromatic deposits in both eyes but no lenticular deposits. Screening of PRDX3 in the proband demonstrated the c.568G>C (p.Asp190His) variant previously associated with PPPCD and failed to identify any variants in PDZD8. CONCLUSIONS: We report the initial confirmation of PRDX3 as the genetic basis of PPPCD in a previously unreported pedigree and expand the phenotype of PPPCD to include polychromatic lenticular deposits.