Molecular Genetics of Cataract

Abstract Cataract can be defined as any opacity or cloudiness of the crystalline lens. When there is significant variation of the refractive index of the lens over distances approximating the wavelength of the transmitted light scattering occurs, resulting in opacity or cataract. Thus, transparency of the crystalline lens requires both orderly arrangement of lens cells and high density of the lens protein constituents. Breakdown of the lens micro‐architecture such as cellular disarray and vacuole formation can cause large fluctuations in optical density of the lens, with resultant cataract. Significant concentrations of high molecular weight protein aggregates of 1000 Å or more in size can also contribute to light scattering. Because 90% of soluble lens proteins is composed of lens crystallins, their short‐range ordered packing in a homogeneous phase and the homoeostatic systems that maintain their stability are critical for maintaining lens transparency. Thus, it is not surprising that approximately 44% of cataract families for whom the mutant gene is known show mutations in lens crystallins with 16% in connexins, 12% in transcription factors, 4% in intermediate filament proteins, 5% in membrane proteins, 5% in chaperones or protein degradation or proofreading proteins, and 6% in a mixed group of other genes, the remainder being unknown. Key Concepts: Cataracts are opacities of the eye lens that result from light scattering either by aggregated proteins within lens cells or disarray of the lens cells themselves. Pathogenesis of inherited cataracts serves to identify critically important developmental, metabolic and biological pathways and processes in the eye lens. Although general trends can be seen with the expression pattern of the causative gene and inherited cataract morphology, identical mutations in the same gene can cause different cataract morphologies and mutations in different genes can result in identical cataract phenotypes. In general, congenital cataracts tend to be caused by mutations that severely disrupt the gene product's structure or function and are thus inherited as highly penetrant Mendelian traits. Conversely, the underlying genetic contributors to age‐related cataracts tend to be less severe mutations that merely impair stability or function and require additional compromise by environmental or modifying genetic factors to cause opacity, so they tend to be multifactorial in their inheritance. Lens crystallins make up 90% of the soluble protein of the eye lens and are thus frequent targets for mutations that destabilise them and cause cataracts. α‐Crystallins are molecular chaperones and can bind denatured proteins, thus preventing or delaying the onset of cataracts, and especially of age‐related cataract. Many other genes implicated in cataractogenesis encode gap junction proteins, solute and aqueous transport proteins, cytoskeletal proteins, developmental transcription factors, membrane proteins, chaperones, or other proteins participating in salvage processes, all important for lens cell development and homoeostasis. In multiple instances, including GALK, EPHA2 and CRYAA, mutations resulting in dramatic destabilization of loss of activity cause congenital cataracts, whereas milder changes contribute to age‐related cataracts in the presence of additional genetic and environmental insults over time.