Mendelian genes in primary open angle glaucoma

Sears, Nathaniel C.; Boese, Erin A.; Miller, Matt; Fingert, John H.

doi:10.1016/j.exer.2019.107702

Cited by 42 publications

(30 citation statements)

References 118 publications

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“…Interestingly, it has been reported that POAG individuals with Glu50Lys mutation in OPTN have primarily exhibited early-onset of severe optic nerve damage that occurs without IOP elevation [147]. Two OPTN mutations, Glu50Lys and Arg545Gln, have been identified in several studies of NTG patients, whereas data confirming the Glu50Lys mutation with NTG pathogenesis are stronger [42,148,149]. It has been reported that NTG patients with the Gln50Lys mutation exhibited a lower level of IOP, larger CDR, more visual field loss, as well as higher rate of surgery than NTG subjects without Gln50Lys mutation [138].…”

Section: Optnmentioning

confidence: 99%

The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma

Rozpędek‐Kamińska

Wojtczak

Szaflik

et al. 2020

IJMS

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Glaucoma is a heterogenous, chronic, progressive group of eye diseases, which results in irreversible loss of vision. There are several types of glaucoma, whereas the primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma, accounting for three-quarters of all glaucoma cases. The pathological mechanisms leading to POAG pathogenesis are multifactorial and still poorly understood, but it is commonly known that significantly elevated intraocular pressure (IOP) plays a crucial role in POAG pathogenesis. Besides, genetic predisposition and aggregation of abrogated proteins within the endoplasmic reticulum (ER) lumen and subsequent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent unfolded protein response (UPR) signaling pathway may also constitute important factors for POAG pathogenesis at the molecular level. Glaucoma is commonly known as a ‘silent thief of sight’, as it remains asymptomatic until later stages, and thus its diagnosis is frequently delayed. Thereby, detailed knowledge about the glaucoma pathophysiology is necessary to develop both biochemical and genetic tests to improve its early diagnosis as well as develop a novel, ground-breaking treatment strategy, as currently used medical therapies against glaucoma are limited and may evoke numerous adverse side-effects in patients.

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Section: Optnmentioning

confidence: 99%

The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma

Rozpędek‐Kamińska

Wojtczak

Szaflik

et al. 2020

IJMS

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“…To improve understanding of how genes associated with glaucoma contribute to disease pathogenesis, we mapped their expression by the 19 cell types in our atlas. We included both known monogenic causes (Mendelian genes) and genes implicated as risk factors in GWAS studies (Wiggs and Pasquale, 2017;Lewis et al,2017;Choquet et al, 2018;Gao et al, 2018;Khawaja et al, 2018;Macgregor et al, 2018;Sears et al, 2019;Youngblood et al, 2019;Krumbiegel et al,2019). Mendelian genes assessed were ANGPT1, ANGPT2,CPAMD8,CYP1B1,FOXC1,LOXL1,LTBP2,MYOC,OPTN,PITX2,TEK (TIE2), and TBK1.…”

Section: Cell-type Specific Expression Patterns Of Glaucoma-associatementioning

confidence: 99%

“…We then used this cell atlas in two ways. First, we assessed expression in each cell type of genes that have been implicated in glaucoma, either as causal genes with Mendelian inheritance or as susceptibility loci identified in genome-wide association studies (GWAS) (Wiggs and Pasquale, 2017;Lewis et al,2017;Choquet et al, 2018;Gao et al, 2018;Khawaja et al, 2018;Macgregor et al, 2018;Sears et al, 2019;Youngblood et al, 2019;Krumbiegel et al,2019), and compared expression levels in cell types of the outflow pathways to those in retinal RGCs and retinal glia (Yan et al, in prep). We found that genes associated with elevated IOP were more likely to be preferentially expressed in the anterior segment, whereas those associated with normal tension glaucoma were more likely to be expressed predominantly in the retina.…”

Section: Introductionmentioning

confidence: 99%

Cell Atlas of Aqueous Humor Outflow Pathways in Eyes of Humans and Four Model Species Provides Insights into Glaucoma Pathogenesis

Zyl

Yan

McAdams

et al. 2020

Preprint

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ABSTRACTIncreased intraocular pressure (IOP) represents a major risk factor for glaucoma, a prevalent eye disease characterized by death of retinal ganglion cells that carry information from the eye to the brain; lowering IOP is the only proven treatment strategy to delay disease progression. The main determinant of IOP is the equilibrium between production and drainage of aqueous humor, with compromised drainage generally viewed as the primary contributor to dangerous IOP elevations. Drainage occurs through two pathways in the anterior segment of the eye, called conventional and uveoscleral. To gain insights into the cell types that comprise these pathways, we used high-throughput single cell RNA sequencing (scRNA-seq). From ∼24,000 single cell transcriptomes, we identified 19 cell types with molecular markers for each and used histological methods to localize each type. We then performed similar analyses on four organisms used for experimental studies of IOP dynamics and glaucoma: cynomolgus macaque (Macaca fascicularis), rhesus macaque (Macaca mulatta), pig (Sus scrofa) and mouse (Mus musculus). Many human cell types had counterparts in these models, but differences in cell types and gene expression were evident. Finally, we identified the cell types that express genes implicated in glaucoma in all five species. Together, our results provide foundations for investigating the pathogenesis of glaucoma, and for using model systems to assess mechanisms and potential interventions.

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“…Following ACMG guidelines for interpretation, we classified the MYOC p.Glu385Lys variant as Likely Pathogenic, based on two moderate and two supporting criteria: PM2 (absent from controls in gnomAD) and PP1_Moderate (cosegregation with disease with multiple family members); and PP3 (multiple lines of computational evidence) and PP4 (specificity of MYOC causing heritable early-onset POAG with elevated IOP, as opposed to other known genetic causes, OPTN and TBK1 , that cause early-onset normal tension glaucoma with IOP ≤ 21 mmHg) (Richards et al 2015; Kelly et al 2018; Sears et al 2019; Wang et al 2019).…”

Section: Technical Analysesmentioning

confidence: 99%

Identification of a novel MYOC variant in a Hispanic family with early-onset primary open-angle glaucoma with elevated intraocular pressure

Criscione

Jeffries

et al. 2019

Cold Spring Harb Mol Case Stud

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Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide. Most cases are multifactorial in etiology, but some are associated with variants in the myocilin gene, MYOC. Here, we report the identification of a novel MYOC variant, c.1153G>A, in a 24-yr-old female patient with a personal and family history of juvenile/early-onset POAG. Further genetic testing within her family demonstrated that this variant segregates with the POAG phenotype in an autosomal dominant pattern. Identification of this MYOC variant in multiple affected relatives provides evidence for its pathogenicity, supporting previous findings linking MYOC mutations, in particular in the third exon's olfactomedin domain, to juvenile-onset POAG. This case also emphasizes the potential value of genetic testing in families with histories of eye disorders.

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Mendelian genes in primary open angle glaucoma

Cited by 42 publications

References 118 publications

The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma

The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma

Cell Atlas of Aqueous Humor Outflow Pathways in Eyes of Humans and Four Model Species Provides Insights into Glaucoma Pathogenesis

Identification of a novel MYOC variant in a Hispanic family with early-onset primary open-angle glaucoma with elevated intraocular pressure

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