The Molecular Basis of Human Anophthalmia and Microphthalmia

Abstract

Human eye development is coordinated through an extensive network of genetic signalling pathways. Disruption of key regulatory genes in the early stages of eye development can result in aborted eye formation, resulting in an absent eye (anophthalmia) or a small underdeveloped eye (microphthalmia) phenotype. Anophthalmia and microphthalmia (AM) are part of the same clinical spectrum and have high genetic heterogeneity, with >90 identified associated genes. By understanding the roles of these genes in development, including their temporal expression, the phenotypic variation associated with AM can be better understood, improving diagnosis and management. This review describes the genetic and structural basis of eye development, focusing on the function of key genes known to be associated with AM. In addition, we highlight some promising avenues of research involving multiomic approaches and disease modelling with induced pluripotent stem cell (iPSC) technology, which will aid in developing novel therapies.

Local retinoic acid directs emergence of the extraocular muscle functional unit

“…(retina), Aldh1a2 (temporal mesenchyme) and Cyp1B1, a member of the cytochrome p450 family of mono-oxygenases which can generate ATRA in the retina in a retinaldehyde dehydrogenease-independent manner (Chambers et al, 2007). Noneless, the severe patterning phenotypes observed in the Aldh1a3 single mutant suggest that the local synthesis of ATRA in the RPE, optic stalk and ventral retina at early stages (≈E10.5) cannot be fully compensated by the action of other retinaldehyde dehydrogeneases in adjacent tissues (this study, (Dupe et al, 2003;Harding and Moosajee, 2019)). Interestingly, the constitutive RARE-hsp68-lacZ transgene displays strong reporter activity in the retina and RPE (Matt et al, 2005;Rossant et al, 1991).…”

“…ATRA is synthetized from retinol through two oxidation steps by specific retinol/alcohol dehydrogenases (RDH/ADH) and retinaldehyde dehydrogenases (ALDH1A1, ALDH1A2 and ALDH1A3) and catabolized into hydroxylated derivatives by enzymes of the cytochrome P450 subfamily (CYP26s) (Cunningham and Duester, 2015;Rhinn and Dolle, 2012). ATRA was shown to be critical for early eye development in several species (Bohnsack et al, 2012;Harding and Moosajee, 2019;See et al, 2008), where the enzymes responsible of ATRA metabolism are expressed in the early retina with tight spatiotemporal patterns (Cvekl and Wang, 2009). Several studies have demostrated that through production of RA, the developing eye acts as a signaling center nucleating anterior segment morphogenesis, with the transcription factor Pitx2 as the potential major downstream effector in periocular NCC (Bohnsack et al, 2012;Matt et al, 2005;Matt et al, 2008;Molotkov et al, 2006).…”

Inherited Eye Diseases with Retinal Manifestations through the Eyes of Homeobox Genes

“…Retinal development in vertebrate embryogenesis is under strict spatial and temporal regulation by the overlapping gene networks [1,29]. Studies on morphological and molecular characteristics of the eye tissues at different stages of human ontogenesis were conducted many years ago and have contributed to the accumulation of information about various aspects of homeobox genes expression [30][31][32][33][34][35].…”

“…Thus, mutations of different genes can lead to pathological changes in the retina characterized by similar phenotypic traits (age-related macular degeneration (AMD), glaucoma, retinitis pigmentosa (RP), etc). Recent evidence shows that the pathogenesis of anophthalmia and microphthalmia share several molecular factors [35]. Pathologies of other parts of the eye often affect the retina.…”

“…Anophthalmia and microphthalmia are part of the same clinical spectrum and have high genetic heterogeneity, with >90 identified associated genes. Currently, mutations in known genes explain less than 40% of these conditions therefore additional causative factors need to be discovered [35]. The MEIS1 gene is the best gap-filling candidate for decoding genetic pathways associated with anophthalmia and microphthalmia.…”