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21 pages, 392 KB

Open AccessReview

Glaucoma Syndromes: Insights into Glaucoma Genetics and Pathogenesis from Monogenic Syndromic Disorders

by Daniel A. Balikov, Adam Jacobson and Lev Prasov

Genes 2021, 12(9), 1403; https://doi.org/10.3390/genes12091403 - 11 Sep 2021

Cited by 16 | Viewed by 6428

Monogenic syndromic disorders frequently feature ocular manifestations, one of which is glaucoma. In many cases, glaucoma in children may go undetected, especially in those that have other severe systemic conditions that affect other parts of the eye and the body. Similarly, glaucoma may be the first presenting sign of a systemic syndrome. Awareness of syndromes associated with glaucoma is thus critical both for medical geneticists and ophthalmologists. In this review, we highlight six categories of disorders that feature glaucoma and other ocular or systemic manifestations: anterior segment dysgenesis syndromes, aniridia, metabolic disorders, collagen/vascular disorders, immunogenetic disorders, and nanophthalmos. The genetics, ocular and systemic features, and current and future treatment strategies are discussed. Findings from rare diseases also uncover important genes and pathways that may be involved in more common forms of glaucoma, and potential novel therapeutic strategies to target these pathways. Full article

(This article belongs to the Special Issue Insights into Heritability of Glaucoma and Other Optic Neuropathies)

15 pages, 3075 KB

Open AccessArticle

Computational Insights into the Structural Dynamics of MDA5 Variants Associated with Aicardi–Goutières Syndrome and Singleton–Merten Syndrome

by Vijayakumar Gosu, Santanu Sasidharan, Prakash Saudagar, Hak-Kyo Lee and Donghyun Shin

Biomolecules 2021, 11(8), 1251; https://doi.org/10.3390/biom11081251 - 21 Aug 2021

Cited by 17 | Viewed by 3991

Abstract

Melanoma differentiation-associated protein 5 (MDA5) is a crucial RIG-I-like receptor RNA helicase enzyme encoded by IFIH1 in humans. Single nucleotide polymorphisms in the IFIH1 results in fatal genetic disorders such as Aicardi–Goutières syndrome and Singleton–Merten syndrome, and in increased risk of type I diabetes in humans. In this study, we chose four different amino acid substitutions of the MDA5 protein responsible for genetic disorders: MDA5^L372F, MDA5^A452T, MDA5^R779H, and MDA5^R822Q and analyzed their structural and functional relationships using molecular dynamic simulations. Our results suggest that the mutated complexes are relatively more stable than the wild-type MDA5. The radius of gyration, interaction energies, and intra-hydrogen bond analysis indicated the stability of mutated complexes over the wild type, especially MDA5^L372F and MDA5^R822Q. The dominant motions exhibited by the wild-type and mutant complexes varied significantly. Moreover, the betweenness centrality of the wild-type and mutant complexes showed shared residues for intra-signal propagation. The observed results indicate that the mutations lead to a gain of function, as reported in previous studies, due to increased interaction energies and stability between RNA and MDA5 in mutated complexes. These findings are expected to deepen our understanding of MDA5 variants and may assist in the development of relevant therapeutics against the disorders. Full article

(This article belongs to the Collection Biomolecules In Silico: Contemporary Advances in Computational Approaches to Investigating the Molecular Dynamics of Biological Systems)

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