Link between a novel human γD-crystallin allele and a unique cataract phenotype explained by protein crystallography

We describe a 5-year-old boy with a unique congenital cataract caused by deposition of numerous birefringent, pleiochroic and macroscopically prismatic crystals. Crystal analysis with subsequent automatic Edman degradation and matrix-associated laser desorption ionization time-of-flight mass spectro...

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Bibliographic Details
Published in:Human molecular genetics 2000-07, Vol.9 (12), p.1779-1786
Main Authors: KMOCH, S, BRYNDA, J, ASFAW, B, BEZOUSKA, K, NOVAK, P, REZACOVA, P, ONDROVA, L, FILIPEC, M, SEDLACEK, J, ELLEDER, M
Format: Article
Language:English
Subjects:
Biological and medical sciences
CRYGD gene
gD-crystallin
Lens diseases
Medical sciences
Ophthalmology
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Summary:We describe a 5-year-old boy with a unique congenital cataract caused by deposition of numerous birefringent, pleiochroic and macroscopically prismatic crystals. Crystal analysis with subsequent automatic Edman degradation and matrix-associated laser desorption ionization time-of-flight mass spectrometry have identified the crystal-forming protein as gamma D-crystallin (CRYGD) lacking the N-terminal methionine. Sequencing of the CRYGD gene has shown a heterozygous C arrow right A transversion in position 109 of the inferred cDNA (36R arrow right S transversion of the processed, N-terminal methionine-lacking CRYGD). The lens protein crystals were X-ray diffracting, and our crystal structure solution at 2.25 Angstrom suggests that mutant R36S CRYGD has an unaltered protein fold. In contrast, the observed crystal packing is possible only with the mutant protein molecules that lack the bulky Arg36 side chain. This is the first described case of human cataract caused by crystallization of a protein in the lens. It involves the third known mutation in the CRYGD gene but offers, for the first time, a causative explanation of the phenotype.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/9.12.1779