OBJECTIVE zeta-crystallin is a quinone oxido-reductase, recruited in the eye lens of hystricomorphic rodents and camels. A deletion mutation constituting the NADPH-binding domain causes congenital cataract in a strain of guinea pigs. The presence of large quantities of a-crystallin, a molecular chaperone, does not provide any protection against this. In order to investigate whether the underlying reason for the lack of protection is the formation of a folding-incompetent protein, we have expressed the mutant protein in a heterologous system along with other known chaperones. METHODS We expressed the mutant zeta-crystallin in E. coli along with other chaperones such as GroEL/ES and DnaK/DnaJ/GrpE and then analyzed whether these chaperones could increase the amount of protein partitioning into the soluble fraction of E. coli cells. RESULTS These chaperones were unable to rescue the mutant protein from partitioning into inclusion bodies, although they could increase the yield of soluble wild-type zeta-crystallin. CONCLUSIONS The deletion of 34 amino acids, constituting the NADPH-binding domain of zeta-crystallin, makes the protein incompetent to fold correctly and thus form insoluble aggregates. It perhaps suggests why the mutant strain of guinea pigs have cataract at birth even though their lenses contain high amounts of alpha-crystallin. This study also shows that certain mutations can render proteins incompetent to fold into soluble molecules despite abundant assistance.