Theoretical Considerations Regarding the Study “Alpha-B Crystallin Gene (CRYAB) Mutation Causes Dominant Congenital Posterior Polar Cataract in Humans”

To the Editor:

In a recently published article (Berry et al. 2001), it was shown that a novel eye lens crystallin mutation of the αB gene (CRYAB) caused dominant well-demarcated congenital posterior polar cataract in a four-generation family of English descent. The described perinatal nonprogressive opacity was confined to the posterior pole of the lens and was 0.5–3 mm in diameter. Sequence analysis of the CRYAB gene revealed a deletion mutation (450delA) that cosegregated with the disease in the family. It was speculated that cataract in this family may have resulted from an increasing tendency of the mutant polypeptide to aggregate and/or from loss of the chaperone-like activity of αB-crystallin, since its protective role in suppressing aggregation of denatured proteins was diminished or lost (Berry et al. 2001).

It is known, however, that during normal lens development, α-crystallins are the first crystallins synthesized in the lens during embryogenesis (Zwaan 1983) and that the lens tissue grows throughout the life span of an individual: new lens fibers develop, and crystallins, including αA- and αB-crystallins, are synthesized continuously. The latter are the most abundant soluble crystallins in the lens and play an important role in maintaining the transparency of the lens (Delaye and Tardieu 1983). If the defective gene CRYAB is responsible for the perinatal posterior nonspreading opacity of the lens, then synthesis of defective proteins should have ceased before and after the perinatal life period, which presumes a temporary self-recovery of the mutation. If, however, the described autosomal dominant perinatal posterior lens opacity is caused solely by the synthesized defective protein, then lens opacity should have also been detectable in the lens embryonic nucleus and should have expanded all over the lens during the later life of the individual, which did not occur. Therefore, it can be supposed that the described defective gene, situated in the CRYAB locus (Berry et al. 2001), may not be the cause for posterior polar nonspreading opacity, since the lens embryonic nucleus and the developing postnatal lens tissue were transparent. Therefore, it is suggested that the described opacities might depend on the temporary persistent primary vitreous, located in Cloquet's canal after the regression of the hyaloid artery during the last trimester of fetal development. Cloquet's canal extends from the optic cup, through the vitreous, to the lens posterior pole. Evidently, compared with the surrounding secondary gel vitreous, the watery content of the temporary persistent primary vitreous facilitates abnormal metabolism of the posterior lens, enabling osmotic and oxidative stresses (Ohta et al. 1999) to reach the lens posterior pole, where they can affect it and cause posterior lens opacity. The localization and size of the described opacity fits well with that of the distal orifice of Cloquet's canal. The fact that the opaque plaque on the lens posterior pole did not expand, irrespective of the persistence of CRYAB gene mutation, serves as strong evidence suggesting that the described novel mutation might be related to the facilitated perinatal metabolism of some substances or to oxidative stress through Cloquet's canal to the lens posterior pole, resulting in the posterior polar opacity. Thus, the deletion mutation might be wholly responsible for the retarded regression of the primary vitreous. The absence of the other ocular or systemic abnormalities in this family history supports this hypothesis.