Adult-onset Primary Open-angle Glaucoma Research Articles

Myocilin Mutation N480K Leads to Early Onset Juvenile and Adult-onset Primary Open Angle Glaucoma in a Six Generation Family.

A pathogenic autosomal dominant MYOC mutation N480K detected in 6 generations of an Indian family is primarily responsible for juvenile open angle glaucoma (JOAG) and adult-onset primary open angle glaucoma (POAG), emphasizing the importance of screening this mutation at a younger age. To screen myocilin mutations in a large South Indian family with early-onset JOAG and adult-onset POAG. In a large South Indian family with 20 members, 8 members diagnosed as JOAG, 7 members as POAG, 4 members as JOAG suspect, and 1 member as POAG suspect were screened for myocilin ( MYOC) mutations using Sanger sequencing. Whole exome sequencing was performed on clinically suspected JOAG/POAG individuals. Myocilin gene mutation N480K (c.1440C>G) was detected in 20 family members, including proband, of whom 8 were JOAG and 7 were POAG patients, 3 were JOAG suspects, and 2 were unaffected. Among the unaffected carriers, 1 was less than 5 years old, and another was 25 years old. The earliest to develop the disease was a 10-year-old child. The penetrance of the mutation was 95% over 10 years of age. This family had JOAG/POAG suspects with no N480K MYOC mutation, and they were further screened for other mutations using whole-exome sequencing. Polymorphisms CYP1B1 L432V and MYOC R76K were detected in 3 JOAG/POAG suspects, and among these 3, one had another CYP1B1 polymorphic variant R368H. The presence of the CYP1B1 polymorphism along with an MYOC polymorphic variant among the JOAG/POAG suspects needs additional studies to explore their combined role in the onset of glaucoma. This study reveals that MYOC mutation is primarily responsible for JOAG and adult-onset POAG in a family, emphasizing the importance of screening for this mutation at a younger age for early treatment.

Gonioscopy-assisted transluminal trabeculotomy for open-angle glaucoma with failed incisional glaucoma surgery: two-year results

BackgroundTo evaluate the safety and efficacy of gonioscopy-assisted transluminal trabeculotomy (GATT) in treating patients with open-angle glaucoma (OAG) who had failed prior incisional glaucoma surgery.MethodsA consecutive case series of OAG patients aged ≥ 18 who underwent GATT with previous failed glaucoma incision surgery was retrospectively analyzed. Main outcome measures included intraocular pressure (IOP), the number of glaucoma medications, surgical success rate, and occurrence of complications. Success was defined as an IOP of ≤ 21 mmHg and a reduction of IOP by 20% or more from baseline with (qualified success) or without (complete success) glaucoma medications. For eyes with preoperative IOP of < 21 mmHg on 3 or 4 glaucoma medications, postoperative IOP of ≤ 18 mmHg without any glaucoma medications was also defined as complete success.ResultsForty-four eyes of 35 patients (21 with juvenile-onset open-angle glaucoma and 14 with adult-onset primary open-angle glaucoma) with a median age of 38 years were included in this study. The proportion of eyes with 1 prior incisional glaucoma surgery was 79.5%, and the others had 2 prior surgeries. IOP decreased from 27.4 ± 8.8 mm Hg on 3.6 ± 0.7 medications preoperatively to 15.3 ± 2.7 mm Hg on 0.5 ± 0.9 medications at the 24-month visit (P < 0.001). The mean IOP and the number of glaucoma medications at each follow-up visit were lower than the baseline (all P < 0.001). At 24 months postoperatively, 82.1% of the eyes had IOP ≤ 18 mmHg (versus 15.9% preoperatively, P < 0.001), 56.4% reached IOP ≤ 15 mmHg (versus 4.6% preoperatively, P < 0.001), and 15.4% achieved IOP ≤ 12 mmHg (compared to none preoperatively, P = 0.009). While 95.5% of eyes took 3 or more medications preoperatively, 66.7% did not take glaucoma medication 24 months after GATT. Thirty-four (77.3%) eyes achieved IOP reduction greater than 20% on fewer medications. The complete and qualified success rates were 60.9% and 84.1%, respectively. No vision-threatening complications occurred.ConclusionsGATT was safe and effective in treating refractory OAG patients who failed prior incisional glaucoma surgery.

Prevalence of Myocilin Gene Mutation in Adult-Onset Primary Open Angle Glaucoma and Non-Glaucoma Subjects Who Are Indigenes of Rivers State, Nigeria

Background: Glaucoma is the leading cause of irreversible blindness incapacitating over 80 million people worldwide. Several pathogenetic mechanisms have been postulated to explain the optic nerve damage that occur in POAG among which genetic predisposition is prominent. Gene-Linkage-based studies have identified genes associated with POAG: Myocilin, Optineurin, WDR36, Tank-Binding Kinase (TBK1) and APbb-2. Objective: To investigate the prevalence of myocilin gene mutation in adult-onset POAG patients and non-glaucoma subjects who are indigenes of Rivers State. Methodology: In this comparative cross-sectional study, 393 POAG patients attending the Glaucoma Clinic of UPTH were compared with 393 age and sex-matched phenotypically normal participants. Clinical assessment combined with findings from clinical records was used. Venous blood was obtained for genomic analyses. Extracted DNA was sequenced with specific primers for myocilin and polymerase chain reaction. Zymo-Bead Genomic DNA kit protocol was used to detect allelic differences. Results: Total of 786 participants participated in the study. The mean age was 59.8 ± 11.8 years. The prevalence of myocilin gene mutation (MYOC) in the study population was 5.3%, in the POAG group was 8.4%, and 2.3% in the non-glaucoma group. This observed difference was statistically significant (p = 0.001). Location of the mutant myocilin gene was in GLC1A 171638779, 171638703, 171638610 and 171638608. Conclusion: Mutations in myocilin gene are associated with adult-onset POAG in Rivers State. Its relevance as a biomarker for diagnosis of adult-onset POAG needs further investigations.

In vivo identification of angle dysgenesis

AbstractAnterior segment Spectral domain–optical coherence tomography (SD‐OCT) is being increasingly used in glaucoma patients, primarily to investigate the anterior chamber angle and visualize the trabecular meshwork (TM) and Schlemm's canal (SC) in vivo. With the advent of angle surgery for glaucoma much interest has been generated in the aqueous outflow pathways. Our studies have shown that in vivo imaging of anterior chamber angle with ASOCT can been used to detect gross features of angle dysgenesis in primary congenital glaucoma (PCG), juvenile onset open angle glaucoma (JOAG) and adult onset primary open angle glaucoma (POAG), which has been described either as an absence of SC and/or the presence of abnormal tissue or a hyper‐reflective membrane within angle recess. This membrane is similar to what Barkan had described in PCG and was later described to be an angle cicatrization that portends a poorer success with goniotomy. Absence of development of SC was also shown by Hollander et al to be associated with a severe form of goniodysgenesis while its presence was seen in less severe goniodysgenesis on histopathological studies involving PCG. In fact, angle dysgenesis on ASOCT (ADoA), can be observed even in eyes with gonioscopically normal appearing angles. It is known that gonioscopy provides only a superficial representation of the histopathological anomalies affecting the angle. The presence of a thick compact tissue in the TM samples of Juvenile glaucoma patients has been observed, irrespective of whether they had an apparent goniodysgenesis or not. Hence, what appears to be morphologically normal angle on gonioscopy may harbour dysgenesis of the TM or even the SC. Primary congenital glaucoma, JOAG and adult onset POAG form a spectrum in terms of severity of angle dysgenesis. While most of the PCG eyes have features of ADoA, the same are present in 40% of JOAG eyes and in up to 35% of adult onset POAG. The size of the SC has also shown to be decreased in patients with adult‐onset open angle glaucoma based on in vivo OCT studies. We also present interesting observations of angle dysgenesis in fellow eyes of children with unilateral PCG.

Demographic and Epidemiological Profile of Patients with Adult-onset Primary Open Angle Glaucoma in a Tertiary Niger-Delta Hospital, Nigeria

Background/Objective: This was a prospective study of patients attending the Glaucoma Clinic at University of Port Harcourt Teaching Hospital, Nigeria and were diagnosed with adult-onset Primary Open Angle Glaucoma (POAG). The objective of the study was to identify and report the demographic and epidemiological characteristics and comorbid states of patients diagnosed with adult-onset POAG. Materials and Methods: Clinical assessment of patients combined with findings from clinical records and interviewer-administered semi-structured questionnaire were used to obtain relevant data from the respondents between January and December 2021. Data collected included demographic data, ethnicity, comorbidity and family history of glaucoma. Results: Eight hundred and fifty(n=850) POAG patients adult aged ≥40 years were recruited in this study. The mean age was 60.5 ± SD 10.1 years. The modal age group was 60-69 years. Seven hundred and seventy-two (n=777; 90.8%) had various forms of visual impairment. Five hundred and twenty-six (n=526; 61.9%) had positive family history of glaucoma in first degree relatives while 120 (14.1%) had positive family history of glaucoma in second degree relatives. Comorbidities associated with adult-onset POAG were cataract (44%), diabetes mellitus (30%) and systemic hypertension (26%). Conclusion: Risk factors for adult-onset POAG in the Niger-Delta are similar to those reported in other black populations in Africa - impaired vision, positive family history of glaucoma, diabetes mellitus, systemic hypertension and cataract. Knowledge of patients’ demographic and epidemiological details are vital for early detection and treatment, thereby reducing the scourge arising from POAG in our population. Keywords: Adult-onset POAG, demographic profile, epidemiological profile, Niger-DeltaRegion, Nigeria.

Ocular Phenotypic Features of Adult-Onset Primary Open Angle Glaucoma in A Tertiary Hospital in Southern Nigeria

Ocular Phenotypic Features of Adult-Onset Primary Open Angle Glaucoma in A Tertiary Hospital in Southern Nigeria

Study of myocillin gene variants alleles in primary open angle glaucoma patients and their first degree relatives in North West Rajasthan, India

Glaucoma is defined as progressive optic neuropathy leading to irreversible blindness if not treated on time. Primary open angle glaucoma (POAG) is most common form of glaucoma. Mutations in myocilin gene (MYOC) account for 2–4% of POAG cases. To identify and evaluate MYOC variants alleles among patients with POAG and their healthy first degree relatives. 66 POAG patients and 26 healthy first degree relatives recruited for study. All patients underwent complete ophthalmic examination followed by genomic DNA (deoxyribonucleic acid) isolation from peripheral blood and quantification of DNA on spectrophotometer. All samples were amplified with each primer by PCR (Polymerase Chain Reaction) technique and amplified DNA and primer sequence checked again by electrophoresis for confirmation of specified MYOC gene mutation. We identified a known MYOC missense mutation, Pro370leu in 16 POAG cases and found consistent genotypic but not phenotypic correlation in 4 of their first degree relatives. Out of 16 cases, pathogenic MYOC gene variant was found in 12 adult onset POAG, 3 juvenile onset POAG, and 1 case of OHT. This study is first of its kind in North India. Our study showed frequency of MYOC gene mutation in POAG cases was 24.24% which is much higher than found elsewhere in India and other countries (2-5%). Frequency of transmission of pathogenic MYOC gene variant in first degree relatives was 25%. The future outcome of our study is promising since early diagnosis and management of high risk family members is possible.

CLINICAL PROFILE AND DEMOGRAPHIC FEATURES OF PATIENTS WITH JUVENILE ONSET OPEN ANGLE GLAUCOMA

Introduction- Juvenile open angle glaucoma (JOAG) is a rare form of glaucoma that differs from adult-onset primary open angle glaucoma (POAG) in its age of onset and often in the magnitude of IOP(intraocular pressure) elevation. Objective-To document the demographic characteristics, clinical features and treatment outcome of patients diagnosed with JOAG. Materials And Methods- A non-comparative retrospective study of patients diagnosed with JOAG in the eye clinic of a tertiary eye care centre was done. Data was taken from clinical records and it included the basic demographic features and the clinical characteristics of the patients and the outcome of their treatment. Results- 30 patients were reviewed of which 9 (29.97%) patients were aged 20 years and below. The mean age was 26.2+/- 5.0 years. 12 (39.96 %) had a visual acuity of 6/18 in the better eye at the time of presentation. 8 (26.64%) patients defaulted within six months of presentation. The mean IOPfor the 22 patients who were followed up on treatment, was 16.35+/- 5.0 mmHg. Conclusion- In this study, most patients with JOAG presented an advance form of disease. Early detection through school eye health program and community-based screening would help in reducing the scourge arising from JOAG.

Histochemical Analysis of Glaucoma Caused by a Myocilin Mutation in a Human Donor Eye

Mutations in myocilin (MYOC) may cause either juvenile open angle glaucoma (JOAG) or adult-onset primary open angle glaucoma (POAG). MYOC encodes a glycoprotein that is normally secreted from trabecular meshwork cells that regulate intraocular pressure. Prior in vitro, transgenic rodent, and organ culture experiments have suggested that abnormal accumulation of MYOC protein within trabecular meshwork cells is a key step in glaucoma pathophysiology. We investigated the pathogenesis of MYOC glaucoma by examining a donor eye from a patient with JOAG caused by a Tyr437His MYOC mutation. Case-control, immunohistochemical study of a donor eye from a patient with JOAG caused by a Tyr437His MYOC mutation and age-matched control donor eyes. An eye from a 59-year-old male with JOAG caused by a Tyr437His MYOC mutation and eyes from five donors (ages 51-66) with no known ocular disease were examined. Frozen fixed sections of the iridocorneal angle were prepared from the donor eyes of the MYOC glaucoma patient and control eyes. We used antibodies directed against MYOC, collagen IV, and BiP/GRP78 as well as wheat germ agglutinin and concanavalin A lectins to localize MYOC protein in the trabecular meshwork. Qualitative comparison of MYOC protein labeling and localization in the trabecular meshwork of donor eyes from a glaucoma patient with a MYOC mutation and from control subjects. Using immunohistochemistry, we detected more abundant MYOC protein within the trabecular meshwork of the MYOC glaucoma patient's eye than in control eyes. We further localized MYOC protein within the trabecular meshwork cells of the MYOC glaucoma patient's eye by co-labeling with the endoplasmic reticulum (ER) marker GRP78 (BiP). Little to no MYOC was identified within the trabecular meshwork cells of control eyes. Minimal extracellular MYOC was detected in both MYOC glaucoma eyes and control eyes. This is the first histopathological analysis of an eye from a glaucoma patient with a MYOC mutation. Furthermore, this analysis supports our model of MYOC-associated glaucoma, in which MYOC mutations cause abnormal intracellular retention of MYOC within the ER of trabecular meshwork cells as a key step towards development of glaucoma.

Analysis of CYP1B1 sequence alterations in patients with primary open-angle glaucoma of Saudi origin.

Cytochrome P450 Family 1 Subfamily B Member 1 (CYP1B1; OMIM# 601771) gene encodes one of the cytochrome P450 family of enzymes. CYP1B1 mutations have been associated primarily with primary congenital glaucoma (PCG). Similar studies were reported in juvenile open-angle glaucoma, Rieger’s and Peters anomalies. Reports of likely pathogenic sequence alterations in families affected with adult-onset primary open-angle glaucoma (POAG) triggered this investigation. We screened unrelated POAG cases and healthy controls for mutations in CYP1B1 using automated Sanger sequencing to identify five known polymorphisms and one CYP1B1 mutation (p.G61E) in a heterozygous status. The p.G61E mutation is known to cause PCG in a homozygous or compound heterozygous form, and thus, its presence here in a heterozygous form indicates carrier status. These findings suggest that CYP1B1 may have no major role in the pathogenesis of POAG, at least, in the Saudi population. However, further investigations are needed to validate these findings in a larger cohort.

Visual Disability Among Juvenile Open-angle Glaucoma Patients.

Juvenile onset primary open-angle glaucoma (JOAG) unlike adult onset primary open-angle glaucoma presents with high intraocular pressure and diffuse visual field loss, which if left untreated leads to severe visual disability. The study aimed to evaluate the extent of visual disability among JOAG patients presenting to a tertiary eye care facility. Visual acuity and perimetry records of unrelated JOAG patients presenting to our Glaucoma facility were analyzed. Low vision and blindness was categorized by the WHO criteria and percentage impairment was calculated as per the guidelines provided by the American Medical Association (AMA). Fifty-two (15%) of the 348 JOAG patients were bilaterally blind at presentation and 32 (9%) had low vision according to WHO criteria. Ninety JOAG patients (26%) had a visual impairment of 75% or more. Visual disability at presentation among JOAG patients is high. This entails a huge economic burden, given their young age and associated social responsibilities.

Glutathione S-transferase M1 polymorphism and primary open-angle glaucoma (POAG) in a Chinese population

Primary Open-Angle Glaucoma (POAG) is a leading cause of irreversible blinding disease. We conducted this case-control study to assess the association between GSTM1 null polymorphism and POAG risk in Chinese. Unrelated 323 adult-onset POAG patients and 295 control subjects were recruited. We found that patients carrying the GSTM1 null genotype had increased risk of POAG (OR=1.80, 95% CI 1.25-2.54, P=0.002). No statistically significantly association was found between GSTM1 polymorphism and smoking status. However, GSTM1 polymorphism was significantly associated with diabetes mellitus in patients. In conclusion, the GSTM1 polymorphism was significantly associated with the risk of POAG.

In Vivo Analysis of Angle Dysgenesis in Primary Congenital, Juvenile, and Adult-Onset Open Angle Glaucoma.

The purpose of this study was to comparatively evaluate angle dysgenesis in vivo, among congenital, juvenile, and adult-onset open angle glaucoma patients. A cross-sectional evaluation of 96 glaucoma patients, 22 children with primary congenital glaucoma (PCG) old enough to cooperate for optical coherence tomography (OCT), 34 juvenile-onset open angle glaucoma (JOAG) patients, 40 adult-onset primary open angle glaucoma (POAG), and 30 healthy subjects, was carried out using high-resolution anterior segment spectral domain (SD)-OCT. Subgroup analysis was done for presence/ absence of angle dysgenesis as defined by presence of abnormal tissue/hyperreflective membrane within angle recess and/or absence of Schlemm's canal (SC). Morphologic features suggestive of angle dysgenesis such as the presence of abnormal tissue at the angle and a hyperreflective membranous structure covering the meshwork were seen in all PCG eyes (100%), in 14 (40%) JOAG eyes, and none of the POAG eyes in comparison to healthy eyes (P = 0.01, P = 0.03, and P = 0.23 for PCG, JOAG, and POAG, respectively). SC could be seen in 27 (90%) healthy eyes compared with only 7 (30%) in PCG (P = 0.01) 20 (60%) JOAG eyes (P = 0.03), and 26 (65%) adult-onset POAG eyes (P = 0.23; χ2 test). Angle dysgenesis in the form of abnormal tissue at the angle/hyperreflective membrane and/or absence of SC could be identified on anterior segment SD-OCT, which can be used for in vivo evaluation of eyes with developmental glaucoma.

Variants in the PRPF8 Gene are Associated with Glaucoma

Glaucoma is the cause of irreversible blindness worldwide. Mutations in six genes have been associated with juvenile- and adult-onset familial primary open angle glaucoma (POAG) prior to this report but they explain only a small proportion of the genetic load. The aim of the study is to identify the novel genetic cause of the POAG in the families with adult-onset glaucoma. Whole exome sequencing (WES) was performed on DNA of two affected individuals, and predicted pathogenic variants were evaluated for segregation in four affected and three unaffected Dutch family members by Sanger sequencing. We identified a pathogenic variant (p.Val956Gly) in the PRPF8 gene, which segregates with the disease in Dutch family. Targeted Sanger sequencing of PRPF8 in a panel of 40 POAG families (18 Pakistani and 22 Dutch) revealed two additional nonsynonymous variants (p.Pro13Leu and p.Met25Thr), which segregate with the disease in two other Pakistani families. Both variants were then analyzed in a case-control cohort consisting of Pakistani 320 POAG cases and 250 matched controls. The p.Pro13Leu and p.Met25Thr variants were identified in 14 and 20 cases, respectively, while they were not detected in controls (p values 0.0004 and 0.0001, respectively). Previously, PRPF8 mutations have been associated with autosomal dominant retinitis pigmentosa (RP). The PRPF8 variants associated with POAG are located at the N-terminus, while all RP-associated mutations cluster at the C-terminus, dictating a clear genotype-phenotype correlation.

Comparison between choroidal thickness in normal and glaucomatous eyes using spectral-domain optical coherence tomography

Purpose The aim of this study was to compare choroidal thickness in healthy and glaucomatous eyes using spectral-domain optical coherence tomography. Patients and methods This prospective study was carried out on patients recruited from the Department of Ophthalmology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt, from April 2015 to April 2016. Informed consent was obtained from all participants. The studied participants were divided into two groups: group 1, which included 100 healthy eyes with normal intraocular pressure, and group 2, which included 100 juvenile and adult-onset primary open-angle glaucomatous eyes. All participants had undergone high-definition raster scanning using spectral-domain optical coherence tomography (Cirrus HD-OCT Model 4000) (software, version 6.0) with frame enhancement software. Choroidal thickness was measured from the posterior edge of the retinal pigment epithelium to the choroid/sclera junction in 11 points. The centre of the fovea (F0) plus five temporal points separated by 500 μm (T0.5, T1.0, T1.5, T2.0 and T2.5) and five nasal points separated by 500 μm (N0.5, N1.0, N1.5, N2.0 and N 2.5) was studied. Statistical analysis of the results was performed using the unpaired t-test. Results Choroidal thickness in group 2 was significantly less than that in group 1 in all studied points with the exception of T0.5 and subfoveal (F0) choroidal thickness. Conclusion The findings of the present study confirmed that choroidal thickness, except for the subfoveal choroidal thickness and 500 μm temporal to the fovea, is significantly less in juvenile and adult-onset primary open-angle glaucoma eyes compared with age-matched normal eyes. Whether this finding represents a risk factor or a consequence of the disease requires further investigations.

Exome Sequencing Identifies a Missense Variant in EFEMP1 Co-Segregating in a Family with Autosomal Dominant Primary Open-Angle Glaucoma.

Primary open-angle glaucoma (POAG) is a clinically important and genetically heterogeneous cause of progressive vision loss as a result of retinal ganglion cell death. Here we have utilized trio-based, whole-exome sequencing to identify the genetic defect underlying an autosomal dominant form of adult-onset POAG segregating in an African-American family. Exome sequencing identified a novel missense variant (c.418C>T, p.Arg140Trp) in exon-5 of the gene coding for epidermal growth factor (EGF) containing fibulin-like extracellular matrix protein 1 (EFEMP1) that co-segregated with disease in the family. Linkage and haplotype analyses with microsatellite markers indicated that the disease interval overlapped a known POAG locus (GLC1H) on chromosome 2p. The p.Arg140Trp substitution was predicted in silico to have damaging effects on protein function and transient expression studies in cultured cells revealed that the Trp140-mutant protein exhibited increased intracellular accumulation compared with wild-type EFEMP1. In situ hybridization of the mouse eye with oligonucleotide probes detected the highest levels of EFEMP1 transcripts in the ciliary body, cornea, inner nuclear layer of the retina, and the optic nerve head. The recent finding that a common variant near EFEMP1 was associated with optic nerve-head morphology supports the possibility that the EFEMP1 variant identified in this POAG family may be pathogenic.

NFATc1 activity regulates the expression of myocilin induced by dexamethasone

Mutations in the myocilin gene (MYOC) account for 10% of juvenile open-angle glaucoma cases and 3–4% of adult onset primary open-angle glaucoma cases. It is a secreted glycoprotein found in many ocular and non-ocular tissues and has been linked to elevated intraocular pressure. In human trabecular meshwork (HTM) cells, MYOC expression can be induced by the glucocorticoid dexamethasone (DEX). In this study we examined the role of the calcineurin/NFATc1 (Nuclear Factor of Activated T-cells) pathway in the DEX induction of MYOC in HTM cells. In post-confluent HTM cells treated with either 500 nM DEX or 0.1% ethanol (EtOH; vehicle control) for 0–6 days both protein and mRNA levels of MYOC were increased while DEX was present. The protein and mRNA levels remained elevated for an additional 12 days after the removal of DEX. Only 1 day of DEX treatment was sufficient to trigger a sustained increase in MYOC mRNA that lasted for 4 days after the removal of DEX. Similar to other studies, myocilin protein expression was not seen until the second day of DEX treatment while mRNA increased within one day of DEX indicating that this is a secondary glucocorticoid response. To determine if MYOC gene expression was regulated by calcineurin/NFATc1, HTM cells were pre-treated for 1 h with the calcineurin inhibitors cyclosporin A or INCA-6 prior to the addition of DEX or EtOH for 2 days. NFATc1 siRNA was used to determine if NFATc1 was required for MYOC mRNA expression. Cells were also treated with the ionophone ionomycin to determine if increased cytosolic calcium affected MYOC expression. These studies showed that the DEX induced increase in MYOC mRNA could be inhibited with either cyclosporin A or INCA-6 or by transfection with NFATc1 siRNA and that ionomycin was unable to increase MYOC mRNA. Immunofluorescence microscopy was also performed to determine if DEX caused the nuclear translocation of NFATc1. Immunostaining showed that NFATc1 relocated to the nucleus within 15 min of DEX treatment and remained there for up to 2 h. The data suggest that the DEX-induced increase in MYOC expression activates a calcineurin and NFATc1 pathway in a calcium independent mechanism.

The Ribosomal Biogenesis Protein Utp21 Interacts with Hsp90 and Has Differing Requirements for Hsp90-Associated Proteins

The molecular chaperone Hsp90 buffers the effects of genetic variation by assisting the stabilization and folding of multiple clients critical for cell signaling and growth. We identified an interaction of Hsp90 and associated proteins with the essential nucleolar protein, Utp21, part of a large complex required for biogenesis of the small ribosomal subunit. The utp21-S602F mutation, which causes minor defects in otherwise wild-type yeast, exhibited severe or lethal growth defects when combined with mutations in Hsp90 or co-chaperones. WT Utp21 and Utp21-S602F exhibited similar interactions with Hsp90, and steady-state levels of WT Utp21 were reduced upon Hsp90 mutation or inhibition. Mutations in the human homolog of UTP21, WDR36, have been associated with adult-onset primary open-angle glaucoma, a leading cause of blindness worldwide. Three different mutant forms of Utp21 analogous to glaucoma-associated WDR36 mutations exhibit reduced levels in yeast cells expressing mutations in Hsp90 or associated chaperones, suggesting that Hsp90 and co-chaperones buffer the effects of those mutations.

Juvenile onset primary open angle glaucoma in members of a single Indian family-A case series

We report a rare case series of bilateral juvenile open-angle glaucoma (JOAG), in three young girls of a same family with discussion of current understanding of its pathogenesis, differential diagnosis, and management. Two sisters named A and B aged 9yrs and 16yrs respectively presented in eye opd chiefly for blurring of vision and were found to have best corrected visual acuity(BCVA)of 6/18both eyes(BE) for A and 6/12,6/24 in right eye(RE) and left eye(LE) respectively for B with normal anterior segment examination. There was an incidental finding of high intra ocular pressure(IOP) in both eyes for both the girls on routine tonometry. Dilated fundus examination revealed normal optic disc and cup disc (CD) ratios with subsequent automated perimetry showing visual field defects in eyes of both the girls.Eldest sister aged 22years was having very poor visual acuity with only hand movement appreciation, IOP was 25.8 mm of hg(BE) with CD ratios of 0.9(RE) and 1(LE).She was on anti glaucoma medications since 1 month and already operated withtrabeculectomy(BE).There was wide open angle on gonioscopy for all the three sisters. Juvenile open-angle glaucoma (JOAG) is a rare form of glaucoma that differs from adult-onset primary open angle glaucoma (POAG) in its age of onset and often in the magnitude of IOP elevation. By definition JOAG has its onset between 3 and 40 years of age, while POAG has its onset after the age of 40. Also, patients with JOAG often have extremely high IOP, sometimes greater than 50 mm Hg. The genetic basis of JOAG is much more obvious than that of POAG.The purpose of reporting this case series is to emphasize the importance of tonometry and ocular examination regardless of patient's age.

Myocilin Mediates Myelination in the Peripheral Nervous System through ErbB2/3 Signaling

The glaucoma-associated gene, myocilin, is expressed in ocular and non-ocular tissues including the peripheral nervous system, but its functions in these tissues remain poorly understood. We demonstrate that in sciatic nerve, myocilin is expressed in Schwann cells with high concentrations at the nodes of Ranvier. There, myocilin interacts with gliomedin, neurofascin, and NrCAM, which are essential for node formation and function. Treatment of isolated dorsal root ganglion cultures with myocilin stimulates clustering of the nodal proteins neurofascin and sodium channel Nav1.2. Sciatic nerves of myocilin null mice express reduced levels of several myelin-associated and basal membrane proteins compared with those of wild-type littermates. They also demonstrate reduced myelin sheath thickness and partial disorganization of the nodes. Myocilin signaling through ErbB2/3 receptors may contribute to these observed effects. Myocilin binds to ErbB2/ErbB3, activates these receptors, and affects the downstream PI3K-AKT signaling pathway. These data implicate a role for myocilin in the development and/or maintenance of myelination and nodes of Ranvier in sciatic nerve.