Molecular and developmental mechanisms of anterior segment dysgenesis

Developmental Biology Unit, University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London, UK.
Eye (Impact Factor: 2.08). 11/2007; 21(10):1310-8. DOI: 10.1038/sj.eye.6702852
Source: PubMed


Anterior segment dysgenesis (ASD) is a failure of the normal development of the tissues of the anterior segment of the eye. It leads to anomalies in the structure of the mature anterior segment, associated with an increased risk of glaucoma and corneal opacity. Several different gene mutations have been identified underlying these anomalies with the majority of ASD genes encoding transcriptional regulators. In this review, the role of the ASD genes, PITX2 and FOXC1, is considered in relation to the embryology of the anterior segment, the biochemical function of these proteins, and their role in development and disease aetiology. The emerging view is that these genes act in concert to specify a population of mesenchymal progenitor cells, mainly of neural crest origin, as they migrate anteriorly around the embryonic optic cup. These same genes then regulate mesenchymal cell differentiation to give rise to distinct anterior segment tissues. Development appears critically sensitive to gene dosage, and variation in the normal level of transcription factor activity causes a range of anterior segment anomalies. Interplay between PITX2 and FOXC1 in the development of different anterior segment tissues may partly explain the phenotypic variability and the genetic heterogeneity characteristic of ASD.

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    • "Key shows the color coding used to represent the embryonic origin of the anterior segment tissues in the right-hand plates, and the pattern of expression of the FOXC1 and PITX2 genes in the left-hand plates, based on published expression data. Reprinted with permission from (Sowden, 2007). "
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    ABSTRACT: The trabecular meshwork (TM) is located in the anterior segment of the eye and is responsible for regulating the outflow of aqueous humor. Increased resistance to aqueous outflow causes intraocular pressure to increase, which is the primary risk factor for glaucoma. TM cells reside on a series of fenestrated beams and sheets through which the aqueous humor flows to exit the anterior chamber via Schlemm's canal. The outer trabecular cells are phagocytic and are thought to function as a pre-filter. However, most of the outflow resistance is thought to be from the extracellular matrix (ECM) of the juxtacanalicular region, the deepest portion of the TM, and from the inner wall basement membrane of Schlemm's canal. It is becoming increasingly evident that the extracellular milieu is important in maintaining the integrity of the TM. In glaucoma, not only have ultrastructural changes been observed in the ECM of the TM, and a significant number of mutations in ECM genes been noted, but the stiffness of glaucomatous TM appears to be greater than that of normal tissue. Additionally, TGFβ2 has been found to be elevated in the aqueous humor of glaucoma patients and is assumed to be involved in ECM changes deep with the juxtacanalicular region of the TM. This review summarizes the current literature on trabecular ECM as well as the development and function of the TM. Animal models and organ culture models targeting specific ECM molecules to investigate the mechanisms of glaucoma are described. Finally, the growing number of mutations that have been identified in ECM genes and genes that modulate ECM in humans with glaucoma are documented. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Experimental Eye Research 04/2015; 133. DOI:10.1016/j.exer.2014.07.014 · 2.71 Impact Factor
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    • "The condition could be isolated or related to a systemic disease. A number of genes have been linked to anterior segment morphogenesis, coding the migration of the neural crest cells, but also regulating mesenchymal cell differentiation of the anterior segment tissues [15,16]. For instance, a paired-like homeodomain transcription factor 2 (PITX2) is associated with Axenfeld-Rieger syndrome [17,18], iridogoniodysgenesis syndrome, and sporadic cases of Peters’ anomaly. "
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    ABSTRACT: Background Williams-Beuren syndrome is characterized by mild mental retardation, specific neurocognitive profile, hypercalcemia during infancy, distinctive facial features and cardiovascular diseases. We report on complete ophthalmologic, sonographic and genetic evaluation of a girl with a clinical phenotype of Williams-Beuren syndrome, associated with unilateral anterior segment dysgenesis and bilateral cleft of the soft and hard palate. These phenotypic features have not been linked to the haploinsufficiency of genes involved in the microdeletion. Case presentation A term born girl presented at the initial examination with clouding of the right cornea. On ultrasound biomicroscopy the anterior chamber structures were difficult to differentiate, showing severe adhesions from the opacified cornea to the iris with a kerato-irido-lenticular contact to the remnant lens, a finding consistent with Peters' anomaly. Genetic analyses including FISH confirmed a loss of the critical region 7q11.23, usually associated with the typical Williams-Beuren syndrome. Microsatellite analysis showed a loss of about 2.36 Mb. Conclusions A diagnosis of Williams-Beuren syndrome was made based on the microdeletion of 7q11.23. The unique features, including unilateral microphthalmia and anterior segment dysgenesis, were unlikely to be caused by the microdeletion. Arguments in favor of the latter are unilateral manifestation, as well as the fact that numerous patients with deletions of comparable or microscopically visible size have not shown similar manifestations.
    BMC Ophthalmology 05/2014; 14(1):70. DOI:10.1186/1471-2415-14-70 · 1.02 Impact Factor
    • "Anterior segment dysgenesis is a group of rare autosomal dominant conditions including posterior embryotoxon, Axenfeld–Rieger syndrome (ARS), Peter's anomaly and aniridia.[1] "
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    ABSTRACT: We report an unusual case of Axenfeld-Rieger Syndrome with secondary glaucoma managed with Ologen(®) implant. A 35-year-old male presented with complaints of decreased vision in both eyes of 22 years duration. His best corrected visual acuity (BCVA) was no perception of light in right eye and 20/30 in left eye. Gonioscopy revealed anterior insertion of iris into trabecular meshwork, prominent iris processes and broad-based synechiae with prominent Schwalbe's line along the angle circumference with cord-like structures taking its origin at the level of Schwalbe's line in both eyes. Fundus examination revealed total glaucomatous optic atrophy in right eye with 0.9:1 cup disc ratio with bipolar notch in left eye. Humphrey visual field analysis showed superior and inferior arcuate scotoma in left eye. Intraocular pressure measured by Goldman applanation tonometry was 30 mmHg and 26 mmHg in right and left eye, respectively. After an unsuccessful medical management, he underwent trabeculectomy with Ologen(®) implant under local anesthesia in his left eye. Postoperatively, at the end of one year, intraocular pressure (IOP) in his left eye was controlled without medication. This case highlights the management of secondary angle closure glaucoma in Axenfeld-Rieger syndrome with Ologen(®) implant.
    Oman Journal of Ophthalmology 05/2014; 7(2):90-2. DOI:10.4103/0974-620X.137170
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