Congenital cataracts and their molecular genetics

Abstract

Cataract can be defined as any opacity of the crystalline lens. Congenital cataract is particularly serious because it has the potential for inhibiting visual development, resulting in permanent blindness. Inherited cataracts represent a major contribution to congenital cataracts, especially in developed countries. While cataract represents a common end stage of mutations in a potentially large number of genes acting through varied mechanisms in practice most inherited cataracts have been associated with a subgroup of genes encoding proteins of particular importance for the maintenance of lens transparency and homeostasis. The increasing availability of more detailed information about these proteins and their functions and is making it possible to understand the pathophysiology of cataracts and the biology of the lens in general. Transparency and the LensThe lens transmits light with wavelengths from 390 nm to 1200 nm efficiently, extending well above the limit of visual perception (about 720 nm). Lens transparency results from appropriate architecture of lens cells and tight packing of their proteins, resulting in a constant refractive index over distances approximating the wavelength of light [1], [2]. Ultrastructurally, the lens comprises an anterior layer of organelle rich cuboidal epithelial cells covering a large fiber cell mass making up the bulk of the lens (Fig. 1). Layers of nucleated cortical fiber cells form highly ordered concentric shells around the nonnucleated and essentially organelle-free central fiber cells which make up the lens nucleus. The ends of the more peripheral fiber cells abut in branched anterior and posterior sutures. The cellular architecture and arrangement of the fiber cells and particularly their sutures are critical for light transmission and lens transparency [3]. In addition, the stability and close ordering of lens crystallins, which make up 80−90% of the soluble proteins in the lens, are critical for lens transparency. The high protein content of the lens and especially the lens nucleus, approximately 60% of the wet weight --the highest of any tissue, is particularly important for refraction and focusing of light. Solutions of lens crystallins are highly transparent, and as they are concentrated to levels above 450 mg/ml, light scattering actually decreases [4], [5].Cataracts, which can be defined as lens opacities, have multiple causes, but are often associated with breakdown of the lens microarchitecture [3], [6], possibly including vacuole formation and disarray of lens cells, which can cause large fluctuations in density resulting in light scattering. In addition, light scattering and opacity will occur if there is a significant amount of high molecular weight protein aggregates of approximately 1000 Å or more in size [7], [8]. The short-range ordered packing of the lens crystallins is important in this regard. For transparency, crystallins must exist in a homogeneous phase with significant short-range spatial Publisher's Disclaimer: This is a PDF file of an un...

How fluorescent labelling alters the solution behaviour of proteins

“…41 Several point mutations in HGD have been linked to congenital cataract formation due to significantly decreased solubility of the protein at body temperature leading to increased light scattering and, eventually, blindness. 37,[40][41][42][43][44] Therefore, LLPS of HGD is a readily quantifiable phase transition through which the effect that the addition of a fluorescent dye, by covalent attachment of an organic fluorophore, can be probed. Additionally, the surface chemistry of HGD ensures that the both the position and number of small molecules conjugated to the protein can be controlled.…”

Cataract-associated mutant E107A of human γD-crystallin shows increased attraction to α-crystallin and enhanced light scattering

“…By comparing the properties of several mutants of HGD in solution with those of the wild type, we have identified specific changes in the homologous (i.e., γ-γ interactions) that led to the formation of distinct condensed phases (6,7) and accounted for the increased light scattering due to these mutations (8)(9)(10)(11)(12)(13). These studies revealed a class of γ-crystallin mutations in which small changes to the protein surface were sufficient to bring about severe solubility changes, without unfolding the protein, and were in direct contrast to other mutations (i.e., other missense mutations, insertions, and splice mutations) that are accompanied by alterations in protein fold and stability (1,14,15).…”

“…T he vertebrate lens contains three families of constituent proteins, the α-, β-, and γ-crystallins, closely packed such that the total protein concentration in the central region of the lens, i.e., nucleus, exceeds 400 mg∕mL (1). Normally, the close protein packing ensures that short-range order is maintained within the fiber cell, such that fluctuations in the refractive index that cause light scattering are minimized, and the lens is transparent (2,3).…”

“…Cataract-associated mutations in the crystallin genes are known to occur in all three crystallin families (1,4) and show a variety of phenotypes. Over the last decade, we have focused on the point mutations occurring in human γD-crystallin (HGD), a member of the γ-crystallin family expressed at high levels along with γC-and γS-crystallins in the human lens (5).…”

Genomic analysis of pediatric cataract in Saudi Arabia reveals novel candidate disease genes

“…This has to be taken into account when one examines available data on the breakdown of pediatric cataract etiology that suggest 10-25% to be genetic in etiology whereas 60% are idiopathic. 6 Within the "genetic" category of pediatric cataract, mutations in crystallins are the most common, accounting for nearly 50% of cases. 7 However, more than 30 loci have been implicated.…”