Cellular and Molecular Mechanisms of Pathogenesis Underlying Inherited Retinal Dystrophies

Abstract

Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The genes associated with these diseases, when mutated, produce altered protein products that have downstream effects in pathways critical to vision, including phototransduction, the visual cycle, photoreceptor development, cellular respiration, and retinal homeostasis. The aim of this manuscript is to provide a comprehensive review of the underlying molecular mechanisms of pathogenesis of IRDs by delving into many of the genes associated with IRD development, their protein products, and the pathways interrupted by genetic mutation.

A Vicious NGF-p75NTR Positive Feedback Loop Exacerbates the Toxic Effects of Oxidative Damage in the Human Retinal Epithelial Cell Line ARPE-19

“…It plays a vital role in the visual cycle, nutrient transport, waste disposal and protection against oxidative stress [27]. Diseases such as retinitis pigmentosa, Stargardt disease and AMD often involve dysfunction or loss of RPE cells [28,29]. Oxidative damage significantly contributes to the degenerative process in these diseases.…”

“…Oxidative damage to the RPE can lead to various detrimental effects, including lipofuscin accumulation, mitochondrial dysfunction, impaired phagocytosis of photoreceptor outer segments and inflammation. These processes contribute to the progressive degeneration of photoreceptors and vision loss [27][28][29]. The distinct effects of hNGF and pNGF on H 2 O 2 -treated ARPE-19 cells were then compared.…”

Mutational Profile and Retinal Phenotypes of PCARE-Related Cone-Rod Dystrophies in a Mexican Cohort

“…IRDs are a paradigmatic example of diseases with phenotypic and genotypic variabilities, as their age of onset, severity of clinical manifestations, and rate of visual loss are considerably variable among individuals and as mutations in over 280 genes can result in the disease [ 3 , 4 ]. IRD-related genes participate in a myriad of cellular processes that are essential for the structural and functional integrity of retinal tissue [ 5 ]. Genetic screening of individuals with IRDs is a crucial procedure for accurate diagnosis, prognosis, and management of patients, and it has been tremendously improved in recent years by the widespread incorporation of next-generation sequencing (NGS) techniques [ 6 , 7 ].…”

Exome sequencing in retinal dystrophy patients reveals a novel candidate gene ER membrane protein complex subunit 3

“…Inherited retinal dystrophies (IRDs) represent a heterogeneous group of visual impairment caused by various pathogenic mutations in genes and regulatory sequences [ 10 , 11 ]. The majority of IRDs are a monogenic and progressive disease.…”

“…The majority of IRDs are a monogenic and progressive disease. Typical IRDs include retinitis pigmentosa (RP), cone-rod dystrophy (CRD), macular degeneration (MD), Leber congenital amaurosis (LCA) and others [ [11] , [12] , [13] , [14] , [15] ]. For example, RP is a group of IRDs characterized by primary degeneration of rod and cone photoreceptors caused mainly by defects in the neural retina and retinal pigment epithelium (RPE) [ [15] , [16] , [17] ].…”