Molecular Genetics of Pigment Dispersion Syndrome and Pigmentary Glaucoma: New Insights into Mechanisms.
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ABSTRACT:
SUBMITTER: Lahola-Chomiak AA
PROVIDER: S-EPMC5892222 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Pigment Dispersion Syndrome (PDS) and Pigmentary Glaucoma (PG) comprise a spectrum of ocular disorders characterized by iris pigment dispersion and trabecular meshwork changes, resulting in increased intraocular pressure and potential glaucomatous optic neuropathy. This review summarizes recent progress in PDS/PG genetics including rare pathogenic protein coding alterations (PMEL) and susceptibility loci identified from genome-wide association studies (GSAP and GRM5/TYR). Areas for future research are also identified, especially the development of efficient model systems. While substantial strides have been made in understanding the genetics of PDS/PG, our review identifies key gaps and outlines the future directions necessary for further advancing this important field of ocular genetics.
| S-EPMC10887877 | biostudies-literature
Project description:PURPOSE: Single nucleotide polymorphisms (SNPs) in the LOXL1 gene have been implicated in exfoliation syndrome (XFS) and exfoliation glaucoma (XFG). We have shown that these SNPs are not associated with the primary glaucomas such as primary open-angle (POAG) glaucoma and primary angle-closure glaucoma (PACG). To further establish the specificity of LOXL1 SNPs for XFS and XFG, we determined whether these SNPs were involved in pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG). METHODS: Three SNPs of LOXL1 (rs1048661, rs3825942, and rs2165241) were screened in a cohort of 78 unrelated and clinically well characterized glaucoma cases comprising of PG (n=44) and PDS (n=34) patients as well as 108 ethnically matched normal controls of Caucasian origin. The criteria for diagnosis of PDS/PG were Krukenberg spindle, hyperpigmentation of the trabecular meshwork, and wide open angle. Transillumination defects were detected by infrared pupillography, and the presence of a Zentmayer ring was considered as a confirmatory sign. All three SNPs were genotyped in cases and controls by resequencing the genomic region of LOXL1 harboring these variants and were further confirmed by polymerase chain reaction (PCR)-based restriction digestions. Haplotypes were generated from the genotype data, and the linkage disequilibrium (LD) and haplotype analysis were done with Haploview software that uses the expectation maximization (EM) algorithm. RESULTS: The LOXL1 SNPs showed no significant association with PDS or PG. There was no significant difference in the frequencies of the risk alleles of rs1048661 ('G' allele; p=0.309), rs3825942 ('G' allele' p=0.461), and rs2165241 ('T' allele; p=0.432) between PG/PDS cases and controls. Similarly, there was no involvement of the XFS/XFG-associated haplotypes, 'G-G' (p=0.643; [OR=1.08, 95%CI, 0.59-1.97]) and 'T-G' (p=0.266; [OR=1.35, 95%CI, 0.70-2.60]), with the PDS/PG phenotypes. The risk haplotype 'G-G' was observed in ~55% of the normal controls. CONCLUSIONS: There was no involvement of the LOXL1 SNPs in patients with PDS and PG. The results further indicate that the associations of these SNPs are specific to XFS/XFG.
| S-EPMC2447814 | biostudies-literature
Project description:BACKGROUND: Single nucleotide polymorphisms (SNPs) within the LOXL1 gene are associated with pseudoesfoliation syndrome and pseudoesfoliation glaucoma. The aim of our study is to investigate a potential involvement of LOXL1 gene in the pathogenesis of pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG). METHODS: A cohort of Caucasian origin of 84 unrelated and clinically well-characterised patients with PDS/PG and 200 control subjects were included in the study. Genomic DNA from whole blood was extracted and the coding and regulatory regions of LOXL1 gene were risequenced in both patients and controls to identify unknown sequence variations. Genotype and haplotype analysis were performed with UNPHASED software. The expression levels of LOXL1 were determined on c-DNA from peripheral blood lymphocytes by quantitative real-time RT-PCR. RESULTS: A significant allele association was detected for SNP rs2304722 within the fifth intron of LOXL1 (Odds ratio (OR = 2.43, p-value = 3,05e-2). Haplotype analysis revealed the existence of risk and protective haplotypes associated with PG-PDS (OR = 3.35; p-value = 1.00e-5 and OR = 3.35; p-value = 1.00e-4, respectively). Expression analysis suggests that associated haplotypes can regulate the expression level LOXL1. CONCLUSIONS: Haplotypes of LOXL1 are associated with PG-PDS independently from rs1048661, leading to a differential expression of the transcript.
| S-EPMC4028282 | biostudies-literature
Project description:Pigmentary glaucoma (PG) is a common glaucoma subtype that results from release of pigment from the iris, called pigment dispersion syndrome (PDS), and its deposition throughout the anterior chamber of the eye. Although PG has a substantial heritable component, no causative genes have yet been identified. We used whole exome sequencing of two independent pedigrees to identify two premelanosome protein (PMEL) variants associated with heritable PDS/PG. PMEL encodes a key component of the melanosome, the organelle essential for melanin synthesis, storage and transport. Targeted screening of PMEL in three independent cohorts (n = 394) identified seven additional PDS/PG-associated non-synonymous variants. Five of the nine variants exhibited defective processing of the PMEL protein. In addition, analysis of PDS/PG-associated PMEL variants expressed in HeLa cells revealed structural changes to pseudomelanosomes indicating altered amyloid fibril formation in five of the nine variants. Introduction of 11-base pair deletions to the homologous pmela in zebrafish by the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 method caused profound pigmentation defects and enlarged anterior segments in the eye, further supporting PMEL's role in ocular pigmentation and function. Taken together, these data support a model in which missense PMEL variants represent dominant negative mutations that impair the ability of PMEL to form functional amyloid fibrils. While PMEL mutations have previously been shown to cause pigmentation and ocular defects in animals, this research is the first report of mutations in PMEL causing human disease.
| S-EPMC6452206 | biostudies-literature
Project description:The molecular mechanisms underlying the pathogenesis of pigment dispersion syndrome and pigmentary glaucoma remain unclear. In pedigree-based studies, familial aggregation and recurrences in relatives suggest a strong genetic basis for pigmentary glaucoma. In this study, we aimed to identify the genetic background of two Chinese pedigrees with pigmentary glaucoma. All members of these two pedigrees who enrolled in the study underwent a comprehensive ophthalmologic examination, and genomic DNA was extracted from peripheral venous blood samples. Whole-exome sequencing and candidate gene verifications were performed to identify the disease-causing variants; in addition, screening of the CPAMD8 gene was performed on 38 patients of sporadic pigmentary glaucoma. Changes in the structure and function of abnormal proteins caused by gene variants were analyzed with a bioinformatics assessment. Pigmentary glaucoma was identified in a total of five patients from the two pedigrees, as were compound heterozygous variants of the CPAMD8 gene. No signs of pigmentary glaucoma were found in carriers of monoallelic CPAMD8 variant/variants. All four variants were inherited in an autosomal recessive mode. In addition to the 38 patients of sporadic pigmentary glaucoma, 13 variants of the CPAMD8 gene were identified in 11 patients. This study reported a possible association between CPAMD8 variants and pigment dispersion syndrome/pigmentary glaucoma.
| S-EPMC9358689 | biostudies-literature
Project description:BackgroundPigment dispersion syndrome (PDS) is characterized by dispersion of pigment in the anterior chamber structures and can present with deposits on the central corneal endothelium or Krukenberg spindle, iris trans-illumination spoke-like defects, and increased pigmentation in the iridocorneal angle. It is more common in myopic patients with a predominance in young males in the third to fifth decade of life that affects about 1-2% of the population. PDS is a risk factor and can give lead to a rise in intraocular pressure (IOP) and secondary glaucoma. Pigmentary glaucoma (PG) can develop from PDS in the presence of elevated IOP coupled with glaucomatous optic neuropathy, retinal nerve fiber thinning, and/or visual field defects. PDS and PG have the same clinical features, representing different levels of severity on the same clinical spectrum.Relevance for patientsEarly diagnosis, appropriate management, and follow-up of patients with PDS are important to prevent vision deterioration or blindness due to glaucomatous optic neuropathy.
| S-EPMC9741933 | biostudies-literature
Project description:Glaucoma is a family of diseases whose pathology is defined by the progressive loss of retinal ganglion cells. Clinically, glaucoma presents as a distinctive optic neuropathy with associated visual field loss. Primary open-angle glaucoma (POAG), chronic angle-closure glaucoma (ACG), and exfoliation glaucoma (XFG) are the most prevalent forms of glaucoma globally and are the most common causes of glaucoma-related blindness worldwide. A host of genetic and environmental factors contribute to glaucoma phenotypes. This review examines the current status of genetic investigations of POAG, ACG, XFG, including the less common forms of glaucoma primary congenital glaucoma (PCG), the developmental glaucomas, and pigment dispersion glaucoma.
| S-EPMC4293633 | biostudies-literature
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| S-EPMC9359298 | biostudies-literature
Project description:Pseudoexfoliation (PEX) syndrome, one of the most common causes of glaucoma, represents a complex, multifactorial, late-onset disease of worldwide significance. The etiopathogenesis involves both genetic and non-genetic factors. The PEX-specific tissue alterations are caused by a generalized fibrotic matrix process, which has been characterized as a stress-induced elastosis associated with the excessive production and abnormal cross-linking of elastic microfibrils into fibrillar PEX aggregates. The identification of lysyl oxidase-like 1 (LOXL1) as a major genetic risk factor for PEX syndrome and PEX glaucoma further supports a role of elastogenesis and elastosis in the pathophysiology of PEX, as LOXL1 is a pivotal cross-linking enzyme in elastic fiber formation and stabilization. The available data suggest that LOXL1 is markedly dysregulated depending on the stage of the fibrotic process. While transient upregulation of LOXL1 during the early stages of PEX fibrogenesis participates in the formation and aggregation of abnormal PEX fiber deposits, the decreased expression of LOXL1 during the advanced stages of the disease may affect elastin metabolism and promote elastotic processes, e.g. in the lamina cribrosa, predisposing to glaucoma development. However, in view of the low penetrance of the PEX-associated risk variants of LOXL1, other genetic and/or environmental factors must contribute to the risk of developing the PEX phenotype. Some evidence exists for the contribution of additional genes with relatively small effects, e.g. clusterin (CLU), contactin-associated protein-like 2 (CNTNAP2), apolipoprotein E (APOE), glutathione S-transferases (GSTs), and tumor necrosis factor-alpha (TNFA), in certain study populations. Several environmental conditions associated with PEX, such as oxidative stress as well as pro-fibrotic cytokines and growth factors, can regulate expression of LOXL1 and elastic proteins in vitro and may therefore act as co-modulating external factors. Ultimately, both detection and functional characterization of yet unidentified genetic and non-genetic factors may lead to the development of more precise screening tools for the risk of PEX glaucoma.
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