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(Investigative Ophthalmology and Visual Science. 2006;47:1069-1075.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-1004
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A Novel {alpha}B-Crystallin Mutation Associated with Autosomal Dominant Congenital Lamellar Cataract

Yizhi Liu,1,2 Xinyu Zhang,1,2,3 Lixia Luo,1 Mingxing Wu,1 Ruiping Zeng,4 Gang Cheng,5 Bin Hu,5 Bingfen Liu,6 Jack J. Liang,6 and Fu Shang3

1From the Zhongshan Ophthalmic Center, the 4Medical Genetic Department, and the 5Daan Gene Diagnosis Center, Sun Yat-sen University, Guangzhou, China; the 3Laboratory for Nutrition and Vision Research, USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts; and the 6Center for Ophthalmic Research, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.

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 {alpha}B-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 {alpha}B-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 {alpha}B-crystallin. Multiangle light-scattering measurement showed that the mutant {alpha}B-crystallin tended to aggregate into a larger complex than did the wild-type. The mutant {alpha}B-crystallin was more susceptible than wild-type to thermal denaturation. Furthermore, the mutant {alpha}B-crystallin not only lost its chaperone-like activity, it also behaved as a dominant negative which inhibited the chaperone-like activity of wild-type {alpha}B-crystallin.

CONCLUSIONS. These data indicate that the altered tertiary and/or quaternary structures and the dominant negative effect of D140N mutant {alpha}B-crystallin underlie the molecular mechanism of cataractogenesis of this pedigree.




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