Progressive juvenile-onset punctate cataracts caused by mutation of the gammaD-crystallin gene

Cataracts are a significant public health problem. Here, we describe the genetic alteration responsible for a progressive form of cataract, segregating as an autosomal dominant trait in a three-generation pedigree. Unlike most autosomal dominant cataracts, these are not clinically apparent at birth...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1999-02, Vol.96 (3), p.1008-1012
Main Authors: Stephan, D A, Gillanders, E, Vanderveen, D, Freas-Lutz, D, Wistow, G, Baxevanis, A D, Robbins, C M, VanAuken, A, Quesenberry, M I, Bailey-Wilson, J, Juo, S H, Trent, J M, Smith, L, Brownstein, M J
Format: Article
Language:English
Subjects:
Age of Onset
Animals
Cataract - genetics
Cataract - physiopathology
Cataracts
Cattle
Crystallins - chemistry
Crystallins - genetics
Exons
Female
Genes
Genetics
Genotype
Humans
Male
Models, Molecular
Mutation
Nuclear Family
Pedigree
Point Mutation
Polymerase Chain Reaction
Polymorphism, Genetic
Polymorphism, Restriction Fragment Length
Polymorphism, Single-Stranded Conformational
Protein Structure, Secondary
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Summary:Cataracts are a significant public health problem. Here, we describe the genetic alteration responsible for a progressive form of cataract, segregating as an autosomal dominant trait in a three-generation pedigree. Unlike most autosomal dominant cataracts, these are not clinically apparent at birth but are initially observed in the first year or two of life. The opacification evolves relatively slowly, generally necessitating removal of the lens in childhood or early adolescence. A genome-wide search in our kindred revealed linkage at 2q33-35 where the gamma-crystallin gene cluster resides. A single base alteration resulting in an Arg- 14 --> Cys (R14C) substitution in gammaD-crystallin was subsequently identified. Protein modeling suggests that the effect of this mutation is a subtle one, affecting the surface properties of the crystallin molecule rather than its tertiary structure, consistent with the fact that the patients' lenses are normal at birth. This is the first gene defect shown to be responsible for a noncongenital progressive cataract, and studying the defective protein should teach us more about the mechanisms underlying cataract formation.
ISSN:0027-8424
1091-6490