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Glaucoma
Published in Ching-Yu Cheng, Tien Yin Wong, Ophthalmic Epidemiology, 2022
Zhi Da Soh, Victor Koh, Ching-Yu Cheng
In addition, genome-wide association studies (GWAS) have identified several single-nucleotide polymorphisms (SNPs) at different loci that are either associated directly with POAG itself, or through its quantitative traits (e.g., IOP, VCDR, CCT).123,124 These loci include, but are not limited to, CAV1/CAV2,125,126TMC01,127CDKN2BAS,127,128SIX6,128,129AFAP1,130GMDS,130ABCA1,130,131PMM2,131TGFBR3,132FNDC3B,132ARHGEF12,133TXNRD2,134ATXN2,134FOXC1,134 and GAS7.134
Embryology of the Female Urogenital System and Clinical Applications
Published in Linda Cardozo, Staskin David, Textbook of Female Urology and Urogynecology - Two-Volume Set, 2017
With current methods of moleculAr biology, the complex chemistry underlying these reciprocAl interActions is being clArified, And severAl exAmples Are offered here. trAnscription fActor PAX2 is expressed during normAl kidney development And ActivAtes Wnt4 gene expression. PAX2 knockout mice Are Anephric, while A heterozygous PAX2 mutAtion results in A 60% decreAse in Wnt4 mrnA [49]. In vitro studies hAve shown thAt gliAl cell–derived neurotrophic fActor (GDnF) secreted by the metAnephric mesenchyme serves to induce ureterAl budding [38]. This is supported by the observAtion thAt the ureters And kidney do not develop in GDnF knockout mice. It hAs Also been shown thAt gene products thAt AntAgonize GDnF expression such As FoXc1 (Figure 22.9) [38] or bMP4 [50] cAn result in multiple bud formAtion And duplex collecting systems. There is Also A role for retinoic Acid–mediAted signAling in the development of the ureterAl buds And trigone As shown in A model using tArgeted deletion of the retinoic Acid receptors [36]. AbnormAl vesicoureterAl development hAs Also been demonstrAted in the presence of tArgeted ret overexpression [51] or the deletion of the type 2 Angiotensin receptor [52].
Embryology
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Nevertheless, UP3 mutations have been identified in a small number of patients with a combination of VUR and severe renal dysplasia (8). Similarly mutations of the PAX 2 gene have been implicated in rare familial cases of VUR (9). The renin-angiotensin system (10) is also known to play an important role in regulating early differentiation and development of the urinary tract. Two types of receptor are responsible for mediating the actions of angiotensin II in target tissues. Stimulation of the angiotensin 1 (AGTR 1) receptor in the embryo promotes cellular proliferation, matrix deposition, and the release of growth factors in the mesenchymal precursors of the kidney and ureter. By contrast, the angiotensin 2 (AGTR2) receptor, which is expressed principally in the embryo and fetus, is responsible for inducing apoptosis and decreased cell growth. “Knockout’’ deletions of the AGTR1 and AGTR2 genes in mice result in different patterns of urinary tract malformations. While deletion of the AGTR1 gene is characterized by progressive dilatation of the collecting system in postnatal life, deletion of AGTR2 gene gives rise to varying degrees of congenital renal hypoplasia, dysplasia, and ureteric dilatation. Some of the many genes now known to be involved in early ureteric development include Gdnf, c-ret, Rara, Agtr2, L1-CAM, Bmp4, Foxc1, Foxc2, Slit 2 Slit 3, Robo, and Pax2 (11).
Whole-exome screening for primary congenital glaucoma in Lebanon
Published in Ophthalmic Genetics, 2023
Nadine J. Makhoul, Zahi Wehbi, Dalia El Hadi, Baha Noureddine, Rose-Mary Boustany, Christiane Al-Haddad
The ocular drainage system derives from the mesenchyme where the forkhead box C1 gene (FOXC1) is expressed (12). In fact, previous descriptions of FOXC1 gene mutations in PCG patients with anterior segment abnormalities exist, and features of Axenfeld-Rieger spectrum were typically revealed in children with FOXC1 pathogenic variants (12) The p.Q92* mutation of the FOXC1 gene was identified in one patient from this cohort. A Mexican patient with Axenfeld-Rieger syndrome (ARS) (65) and a Vietnamese patient with ASD and congenital glaucoma carried this mutation (16). This mutation leads to a premature termination codon at position 92 of the protein. The truncated region affects the DNA-binding domain and the Nuclear Localization Signal 1 (NLS1) motif of the fork head domain of the FOXC1 protein. An analysis of FOXC1 variants in 133 pedigrees with PCG in 2016 demonstrated that FOXC1 mutations may effect goniodysgenesis in PCG (14). FOXC1 variants were associated with PCG frequently complicated with Axenfeld-Rieger syndrome (hearing loss, heart murmur and developmental delay). Two point mutations of FOXC1 and PITX2 genes were identified in individuals with abnormal development of iris tissue (16). This cohort included a patient who presented at 1 week of age; agreeing with finding mutations in the FOXC1 gene causative of early-onset glaucomas (15). He also has a younger affected brother with PCG and a cousin with signs of Axenfeld-Rieger spectrum: posterior embryotoxon and corectopia.
Association of variants in the ATXN2 (rs7137828), FOXC1 (rs2745572) and TXNRD2 (rs35934224) genes as risk factors for primary open-angle glaucoma development in a Brazilian cohort
Published in Ophthalmic Genetics, 2023
Thiago Adalton Rosa Rodrigues, Bruno Batista de Souza, Victor de Haidar e Bertozzo, Júlia Nicoliello Pereira de Castro, Ana Carolina Lima Camargo, Fernando Ferreira Costa, Rui Barroso Schimiti, Vital Paulino Costa, José Paulo Cabral de Vasconcellos, Mônica Barbosa de Melo
The ATXN2 gene is located on chromosome 12q24.12, and encodes the protein ataxin-2, which is responsible for microsatellite-expansion diseases (18). The FOXC1 gene (6p25.3) is a protein-coding gene member of the forkhead family of transcription factors, whose rare coding-sequence variations are associated with a critical dysfunction in the embryonic brain and eye development including anterior segment dysgenesis (19,20). The TXNRD2 gene (22q11.21) belongs to the thioredoxin (Trx) system, a relevant mitochondrial protein found in mammals. This protein controls redox homeostasis, decreasing the levels of harmful reactive oxygen species (ROS) produced by oxidative phosphorylation, second to other mitochondrial functions (21,23,24). Most studies on the genetic basis of glaucoma were conducted in Caucasian or Asian populations, which exhibit a homogeneous genetic profile. Due to a high incidence of multiple migrations, resulting from more than five centuries of intersection among three main ancestral roots (Amerindians, Europeans, and Africans), the Brazilian population presents a unique ethnic profile that is worth investigating (25,26). These genetic attributes characterize the Brazilian population as a relevant model for potential insights into POAG discovery once our population is under-represented in ophthalmic genetics research worldwide (25).
Mutation Survey of Candidate Genes and Genotype–Phenotype Analysis in 20 Southeastern Chinese Patients with Axenfeld–Rieger Syndrome
Published in Current Eye Research, 2018
Xun Wang, Xing Liu, Liqin Huang, Shaohua Fang, Xiaoyun Jia, Xueshan Xiao, Shiqiang Li, Xiangming Guo
ARS is genetically heterogeneous, and approximately 40% of patients with ARS have been found to harbor mutations. The major candidate genes for ARS are PITX2 and FOXC1. PITX2 is a member of the bicoid-like homeobox transcription factor family.5 It plays a fundamental role in the genetic control of ocular anterior segment development.6,7FOXC1 is a member of the forkhead family of transcription factors. It acts as an important regulator of cell migration and differentiation during embryogenesis.8PITX2 and FOXC1 mutations are found in almost 40% of ARS patients.9 Both iris malformations and effects on the trabecular meshwork are variable in patients with ARS who have mutations in these two genes.10 A third chromosomal locus at 13q14 may also be associated with ARS.11,12 However, no candidate genes have been detected in this region. More than 50% of patients with ARS do not harbor mutations in these two genes. Recently, a whole-exome sequencing study reported that variants in the PRDM5 gene were associated with anterior segment defects, such as ARS, in a Pakistani family.13 The relationship between PRDM5 and ARS in other populations requires further study.