A locus for a human hereditary cataract is closely linked to the γ-crystallin gene family

Within the human γ-crystallin gene cluster polymorphic Taq I sites are present. These give rise to three sets of allelic fragments from the γ-crystallin genes. Together these restriction fragment length polymorphisms define eight possible haplotypes, three of which (Q, R, and S) were found in the Dutch and English population. A fourth haplotype (P) was detected within a family in which a hereditary Coppock-like cataract of the embryonic lens nucleus occurs in heterozygotes. Haplotype P was found only in family members who suffered from cataract, and all family members who suffered from cataract had haplotype P. The absolute correlation between the presence of haplotype P and cataract within this family shows that the γ-crystallin gene cluster and the locus for the Coppock-like cataract are closely linked [logarithm of odds (lod) score of 7.58 at its maximum at θ = 0]. This linkage provides genetic evidence that the primary cause of a cataract in humans could possibly be a lesion in a crystallin gene.link_to_OA_fulltex

X-ray Analysis of B2-Crystallin and Evolution of Oligomeric Lens Proteins.

THE β, γ-crystallins form a class of homologous proteins in the eye lens. Each γ-crystallin comprises four topologically equivalent, Greek key motifs; pairs of motifs are organized around a local dyad to give domains and two similar domains are in turn related by a further local dyad1–4. Sequence comparisons and model building predicted that hetero-oligomeric β-crystallins also had internally quadruplicated subunits, but with extensions at the N and C termini, indicating that β, γ-crystallins evolved in two duplication steps from an ancestral protein folded as a Greek key5–7. We report here the X-ray analysis at 2.1 Å resolution of βB2-crystall in homodimer which shows that the connecting peptide is extended and the two domains separated in a way quite unlike γ-crystallin. Domain interactions analogous to those within monomeric γ-crystallin are intermolecular and related by a crystallographic dyad in the βB2-crystallin dimer. This shows how oligomers can evolve by conserving an interface rather than connectivity. A further interaction between dimers suggests a model for more complex aggregates of β-crystallin in the len

Explosive expansion of βγ-Crystallin genes in the ancestral vertebrate

In jawed vertebrates, βγ-crystallins are restricted to the eye lens and thus excellent markers of lens evolution. These βγ-crystallins are four Greek key motifs/two domain proteins, whereas the urochordate βγ-crystallin has a single domain. To trace the origin of the vertebrate βγ-crystallin genes, we searched for homologues in the genomes of a jawless vertebrate (lamprey) and of a cephalochordate (lancelet). The lamprey genome contains orthologs of the gnathostome βB1-, βA2- and γN-crystallin genes and a single domain γN-crystallin-like gene. It contains at least two γ-crystallin genes, but lacks the gnathostome γS-crystallin gene. The genome also encodes a non-lenticular protein containing βγ-crystallin motifs, AIM1, also found in gnathostomes but not detectable in the uro- or cephalochordate genome. The four cephalochordate βγ-crystallin genes found encode two-domain proteins. Unlike the vertebrate βγ-crystallins but like the urochordate βγ-crystallin, three of the predicted proteins contain calcium-binding sites. In the cephalochordate βγ-crystallin genes, the introns are located within motif-encoding region, while in the urochordate and in the vertebrate βγ-crystallin genes the introns are between motif- and/or domain encoding regions. Coincident with the evolution of the vertebrate lens an ancestral urochordate type βγ-crystallin gene rapidly expanded and diverged in the ancestral vertebrate before the cyclostomes/gnathostomes split. The β- and γN-crystallin genes were maintained in subsequent evolution, and, given the selection pressure imposed by accurate vision, must be essential for lens function. The γ-crystallin genes show lineage specific expansion and contraction, presumably in adaptation to the demands on vision resulting from (changes in) lifestyle