Many forms of congenital hereditary cataract are associated with mutations in the crystallin genes. The authors focus attention on congenital lamellar cataract, which is associated with the R168W mutation in gammaC-crystallin, and congenital zonular pulverulent cataract, which is associated with a 5-bp insertion in the gammaC-crystallin gene.To understand the molecular phenotypes-i.e., the functional defects that have occurred in the mutant gammaC-crystallin molecule in two cases described-the authors cloned, expressed, isolated, and compared the solution state structural features of these mutants with those of normal (wild-type) gammaC-crystallin. Structural models of the wild-type and mutant have been generated using comparative modeling. Circular dichroism and fluorescence spectroscopic methods were used to determine the conformation of the proteins, and temperature dependent self-aggregation was used to observe the quaternary structural features. The structural stability of the proteins was monitored with the use of chemical and thermal denaturation.The authors found that the 5-bp insertion led to a loss of secondary and tertiary structures of the molecule and to an enhanced tendency of self-aggregation into light-scattering particles, offering a possible factor in lens opacification. The R168W mutant, on the other hand, was remarkably similar to the wild-type molecule in its conformation and structural stability, but it differed in its ability to aggregate and scatter light.These results support the idea that unfolding or structural destabilization is not always necessary for crystallin-associated cataractogenesis.