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Human Molecular Genetics, 2000, Vol. 9, No. 12 1779-1786
© 2000 Oxford University Press

Link between a novel human {gamma}D-crystallin allele and a unique cataract phenotype explained by protein crystallography

Stanislav Kmoch, Jirí Brynda1, Befekadu Asfaw, Karel Bezouska2, Petr Novák3, Pavlína Rezácová1, Lenka Ondrová, Martin Filipec4, Juraj Sedlácek1 and Milan Elleder+

Institute of Inherited Metabolic Diseases, Division B, Building D, Ke Karlovu 2, 12808 Prague 2, Czech Republic, 1Department of Gene Manipulation, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic, 2Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic, 3Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic and 4Ophthalmologic Clinic, Charles University, 1st Faculty of Medicine and University Hospital, Prague, Czech Republic

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->A transversion in position 109 of the inferred cDNA (36R->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 Å 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.

+ To whom correspondence should be addressed. Tel: +420 2 2491 8283; Fax: +420 2 2491 9392; Email: melleder@beba.cesnet.cz


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