Temperature-dependent structural and functional properties of a mutant (F71L) αA-crystallin: Molecular basis for early onset of age-related cataract

Validandi, Vakdevi; Reddy, Vinodini; Srinivas, Pooja; Mueller, Niklaus H.; Bhagyalaxmi, S.G.; Padma, T.; Petrash, J. Mark; Reddy, G. Bhanuprakash

doi:10.1016/j.febslet.2011.10.049

Cited by 14 publications

(9 citation statements)

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“…It is believed that oxidative stress, osmotic stress, and nonenzymatic glycation of lens proteins result in altered structural and functional integrity either due to direct modification and/or due to reduced a-crystallin chaperone activity, resulting in lens protein aggregation and thus opacification (13)(14)(15)28). Heat, chemical-or UV-induced aggregation of lens proteins in vitro has been used to study the factors leading to cataract formation in vivo, as in vitro observations are well correlated with that of cataract progression in vivo.…”

Section: Figmentioning

confidence: 99%

Increased risk of cataract development in WNIN‐obese rats due to accumulation of intralenticular sorbitol

et al. 2013

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Epidemiological studies have reported an association between obesity and increased incidence of ocular complications including cataract, yet the underlying biochemical and molecular mechanisms remained unclear. Previously we had demonstrated accumulation of sorbitol in the lens of obese rats (WNIN/Ob) and more so in a related strain with impaired glucose tolerance (WNIN/GR-Ob). However, only a few (15-20%) WNIN/Ob and WNIN/GR-Ob rats develop cataracts spontaneously with age. To gain further insights, we investigated the susceptibility of eye lens proteins of these obese rat strains to heat-and UV-induced aggregation in vitro, lens opacification upon glucose-mediated sorbitol accumulation ex vivo, and onset and progression of cataract was followed by galactose feeding and streptozotocin (STZ) injection. The results indicated increased susceptibility toward heat-or UV-induced aggregation of lens proteins in obese animals compared to their littermate lean controls. Further, in organ culture studies glucose-induced sorbitol accumulation was found to be higher and thus the lens opacification was faster in obese animals compared to their lean littermates. Also, the onset and progression of galactose-or STZ-induced cataractogenesis was faster in obese animals compared to lean control. These results together with our previous observations suggest that obesity status could lead to hyperaccumulation of sorbitol in eye lens, predisposing them to cataract, primarily by increasing their susceptibility to environmental and/or physiological factors. Further, intralenticular sorbitol accumulation beyond a threshold level could lead to cataract in WNIN/Ob and WNIN/ GR-Ob rats. V C 2013 IUBMB Life, 65(5): [472][473][474][475][476][477][478] 2013

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Section: Figmentioning

confidence: 99%

Increased risk of cataract development in WNIN‐obese rats due to accumulation of intralenticular sorbitol

et al. 2013

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“…These genes include EPHA2 (1p), GJA3 (13q), GJA8 (1q), MIP (12q), HSF4 (16q), LIM2 (19q), and CRYAA (21q). 46–50 However, only the EPHA2 association has been replicated in different populations including with cortical cataract in Caucasians and Han Chinese, with cortical cataract and PSC in Indians, and with any cataract in Caucasians and Asians from China and India. 46,51–54 There was no association of EPHA2 variants with nuclear cataract in any population.…”

Section: Genes Associated With Age-related Cataractmentioning

confidence: 99%

Molecular Genetics of Cataract

Shiels

Hejtmancik

2015

Progress in Molecular Biology and Translational Science

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Lens opacities or cataract(s) represent a universally important cause of visual impairment and blindness. Typically, cataract is acquired with aging as a complex disorder involving environmental and genetic risk factors. Cataract may also be inherited with an early onset either in association with other ocular and/or systemic abnormalities or as an isolated lens phenotype. Here we briefly review recent advances in gene discovery for inherited and age-related forms of cataract that are providing new insights into lens development and aging.

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“…These genes include EPHA2 (1p), GJA3 (13q), GJA8 (1q), MIP (12q), HSF4 (16q), LIM2 (19q), and CRYAA (21q). [46][47][48][49][50] However, only the EPHA2 association has been replicated in different populations including with cortical cataract in Caucasians and Han Chinese, with cortical cataract and PSC in Indians, and with any cataract in Caucasians and Asians from China and India. 46,[51][52][53][54] There was no association of EPHA2 variants with nuclear cataract in any population.…”

Section: Genes Associated With Age-related Cataractmentioning

confidence: 99%

Molecular Genetics of Cataract

Shiels

Hejtmancik

2014

Encyclopedia of Life Sciences

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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.

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Temperature-dependent structural and functional properties of a mutant (F71L) αA-crystallin: Molecular basis for early onset of age-related cataract

Cited by 14 publications

References 34 publications

Increased risk of cataract development in WNIN‐obese rats due to accumulation of intralenticular sorbitol

Increased risk of cataract development in WNIN‐obese rats due to accumulation of intralenticular sorbitol

Molecular Genetics of Cataract

Molecular Genetics of Cataract

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