A Novel AlphaB-crystallin Mutation Associated with Autosomal Dominant Congenital Lamellar Cataract

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2006 Mar 1

PMID 16505043

Citations 56

Authors

Yizhi Liu

Xinyu Zhang

Lixia Luo

Mingxing Wu

Ruiping Zeng

Gang Cheng

Bin Hu

Bingfen Liu

Jack J Liang

Fu Shang

Affiliations

Soon will be listed here.

Abstract

Purpose: To identify the mutation and the underlying mechanism of cataractogenesis in a five-generation autosomal dominant congenital lamellar cataract family.

Methods: Nineteen mutation hot spots associated with autosomal dominant congenital cataract have been screened by PCR-based DNA sequencing. Recombinant wild-type and mutant human alphaB-crystallin were expressed in Escherichia coli and purified to homogeneity. The recombinant proteins were characterized by far UV circular dichroism, intrinsic tryptophan fluorescence, Bis-ANS fluorescence, multiangle light-scattering, and the measurement of chaperone activity.

Results: A novel missense mutation in the third exon of the alphaB-crystallin gene (CRYAB) was found to cosegregate with the disease phenotype in a five-generation autosomal dominant congenital lamellar cataract family. The single-base substitution (G-->A) results in the replacement of the aspartic acid residue by asparagine at codon 140. Far UV circular dichroism spectra indicated that the mutation did not significantly alter the secondary structure. However, intrinsic tryptophan fluorescence spectra and Bis-ANS fluorescence spectra indicated that the mutation resulted in alterations in tertiary and/or quaternary structures and surface hydrophobicity of alphaB-crystallin. Multiangle light-scattering measurement showed that the mutant alphaB-crystallin tended to aggregate into a larger complex than did the wild-type. The mutant alphaB-crystallin was more susceptible than wild-type to thermal denaturation. Furthermore, the mutant alphaB-crystallin not only lost its chaperone-like activity, it also behaved as a dominant negative which inhibited the chaperone-like activity of wild-type alphaB-crystallin.

Conclusions: These data indicate that the altered tertiary and/or quaternary structures and the dominant negative effect of D140N mutant alphaB-crystallin underlie the molecular mechanism of cataractogenesis of this pedigree.

Citing Articles

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Association of Alpha-Crystallin with Human Cortical and Nuclear Lens Lipid Membrane Increases with the Grade of Cortical and Nuclear Cataract.

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Structural and functional studies of D109A human αB-crystallin contributing to the development of cataract and cardiomyopathy diseases.

Hafizi M, Chebotareva N, Ghahramani M, Moosavi-Movahedi F, Khaleghinejad S, Kurganov B PLoS One. 2021; 16(11):e0260306.

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Inherited cataracts: Genetic mechanisms and pathways new and old.

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