Inherited Congenital Cataract: A Guide to Suspect the Genetic Etiology in the Cataract Genesis

Messina-Baas, Olga; Cuevas-Covarrubias, Sergio A.

doi:10.1159/000455752

Cited by 69 publications

(67 citation statements)

References 190 publications

(88 reference statements)

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“…This scenario is certainly not implausible since there are hundreds of instances of congenital cataract resulting from one amino acid substitution in a single crystallin. 49 It could be that an amount of deamidation above a certain level at these specific sites within an already highly modified crystallin background acts as ''the straw that broke the camel's back'' to cause these lenses to opacify.…”

Section: Can Deamidation Of Certain Key Asn Residues Precipitate Catamentioning

confidence: 99%

Molecular Processes Implicated in Human Age-Related Nuclear Cataract

Truscott

Friedrich

2019

Invest. Ophthalmol. Vis. Sci.

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Human age-related nuclear cataract is commonly characterized by four biochemical features that involve modifications to the structural proteins that constitute the bulk of the lens: coloration, oxidation, insolubility, and covalent cross-linking. Each of these is progressive and increases as the cataract worsens. Significant progress has been made in understanding the origin of the factors that underpin the loss of lens transparency. Of these four hallmarks of cataract, it is protein-protein cross-linking that has been the most intransigent, and it is only recently, with the advent of proteomic methodology, that mechanisms are being elucidated. A diverse range of cross-linking processes involving several amino acids have been uncovered. Although other hypotheses for the etiology of cataract have been advanced, it is likely that spontaneous decomposition of the structural proteins of the lens, which do not turn over, is responsible for the age-related changes to the properties of the lens and, ultimately, for cataract. Cataract may represent the first and best characterized of a number of human agerelated diseases where spontaneous protein modification leads to ongoing deterioration and, ultimately, a loss of tissue function.

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Section: Can Deamidation Of Certain Key Asn Residues Precipitate Catamentioning

confidence: 99%

Molecular Processes Implicated in Human Age-Related Nuclear Cataract

Truscott

Friedrich

2019

Invest. Ophthalmol. Vis. Sci.

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“…Approximately half of the congenital cataracts are characterised as inherited and are a clinical feature of nearly 200 syndromic genetic diseases, 4 including for instance diabetes and cholesterol metabolism diseases. Congenital cataract was the first autosomal disease to be genetically mapped in humans 5 and has subsequently been shown to be associated with considerable genetic and phenotypic heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Inherited cataracts: molecular genetics, clinical features, disease mechanisms and novel therapeutic approaches

et al. 2020

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Cataract is the most common cause of blindness in the world; during infancy and early childhood, it frequently results in visual impairment. Congenital cataracts are phenotypically and genotypically heterogeneous and can occur in isolation or in association with other systemic disorders. Significant progress has been made in identifying the molecular genetic basis of cataract; 115 genes to date have been found to be associated with syndromic and non-syndromic cataract and 38 disease-causing genes have been identified to date to be associated with isolated cataract. In this review, we briefly discuss lens development and cataractogenesis, detail the variable cataract phenotypes and molecular mechanisms, including genotype-phenotype correlations, and explore future novel therapeutic avenues including cellular therapies and pharmacological treatments.

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“…Cataract causes clouding of normal clear lenses and has been known as the cause for half of all cases of human blindness and one‐third of the ocular damages in the world . The incidence rates of 1 to 15 per 10 000 live births have been reported for congenital cataract disorders .…”

Section: Introductionmentioning

confidence: 99%

“…These genes code for crystallin proteins, connexin, transcription factors, membrane transport proteins and cytoskeletal proteins. Statistically, development of congenital cataracts corresponds to larger number of the mutations in CRYAA than to small number in CRYAB . However, CRYAB gene mutations have been known to cause desmin‐related myopathy, myofibrillar myopathy and dilated cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

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The congenital cataract‐causing mutations P20R and A171T are associated with important changes in the amyloidogenic feature, structure and chaperone‐like activity of human αB‐crystallin

et al. 2020

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Cataract is the major reason for human blindness worldwide. α-Crystallin, as a key chaperone of eye lenses, keeps the lenticular tissues in its transparent state over time.In this study, cataract-causing familial mutations, P20R and A171T, were introduced in CRYАB gene. After successful expression in Escherichia coli and subsequent purification, the recombinant proteins were subjected to extensive structural and functional analyses using various spectroscopic techniques, gel electrophoresis, and electron microscopy.The results of fluorescence and Raman assessments suggest important but discreet conformational changes in human αB-Cry upon these cataractogenic mutations.Furthermore, the mutant proteins exhibited significant secondary structural alteration as revealed by FTIR and Raman spectroscopy. An increase in conformational stability was seen in the human αB-Cry bearing these congenital cataractogenic mutations. The oligomeric size distribution and chaperone-like activity of human αB-Cry were significantly altered by these mutations. The P20R mutant protein was observed to loose most of the chaperone-like activity. Finally, these cataractogenic mutant proteins exhibited an increased propensity to form the amyloid fibrils when incubated under environmental stress. Overall, the structural and functional changes in mutated human αB-Cry proteins can shed light on the pathogenic development of congenital cataracts. K E Y W O R D Scataract, chaperone activity, human αB-Cry, mutation, structure 1 | INTRODUCTION α-Crystallin (α-Cry) is a stable β-sheet rich protein with relatively low turnover. It accounts for 40% of the total soluble proteins of the lenticular tissues. This guardian protein of the eye lenses is a member of the small heat shock protein (sHSP) family that binds selectively to the unfolded proteins. α-Cry thus suppresses protein aggregation and keeps the lenticular tissues in its transparent state during aging. [1][2][3][4][5][6][7] In the lenticular tissues, 30 to 40 subunits of α-Cry (αA and αB) assemble in the ratio of 3:1, respectively, and form polydisperse hetero-oligomeric ensembles. [8][9][10] In humans, αA (173 residues) and αB (175 residues) are coded by CRYAA and CRYАB genes which are located on chromosomes 21 and 11, respectively. Human αA and αB share 57% sequence homology [4,11] and both contain three domains. In each subunit the highly conserved central α-Cry domain (ACD) (90-100 residues), characteristic of the sHSP family, links the conformationally flexible N-terminal domain (NTD) to a C-terminal domain (CTD) rich in charged residues. [12,13] While the ACD with its chaperone activity prevents the selfassembly of different protein aggregates, [14] the NTD and CTD maintain the oligomerization and solubility of the client proteins. [15]

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Inherited Congenital Cataract: A Guide to Suspect the Genetic Etiology in the Cataract Genesis

Cited by 69 publications

References 190 publications

Molecular Processes Implicated in Human Age-Related Nuclear Cataract

Molecular Processes Implicated in Human Age-Related Nuclear Cataract

Inherited cataracts: molecular genetics, clinical features, disease mechanisms and novel therapeutic approaches

The congenital cataract‐causing mutations P20R and A171T are associated with important changes in the amyloidogenic feature, structure and chaperone‐like activity of human αB‐crystallin

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