In a case-control study, Zurdel et al. (2002) investigated whether haplotypes A or B of the cystatin C gene were genetically associated with exudative age-related macular degeneration in a Caucasian population. Cystatin C is a cysteine protease inhibitor ... In a case-control study, Zurdel et al. (2002) investigated whether haplotypes A or B of the cystatin C gene were genetically associated with exudative age-related macular degeneration in a Caucasian population. Cystatin C is a cysteine protease inhibitor that regulates the activity of cathepsin S (116845), a protease with central regulatory functions in retinal pigment epithelial (RPE) cells. They found no significant difference in allele frequencies between patients and controls. There was a significant difference in genotype counts between patients and controls, which could be explained completely by an excess of the homozygous CST3 genotype B/B (ala25-to-thr; 604312.0002) in patients (6.6%) over controls (2.3%), suggesting an odds ratio for ARMD in association with CST3 B/B of 2.97 (95% CI, 1.28-6.86). The mean disease-free survival time in pooled males and females with genotypes A/A or A/B was 85 years, and with genotype B/B, 76 years. Zurdel et al. (2002) concluded that CST3 haplotype B may be a recessive risk allele, significantly contributing to disease risk in up to 6.6% of German ARMD patients. Paraoan et al. (2004) found that proper targeting of cystatin C to the Golgi apparatus and processing through the secretory pathway of RPE cells was dependent upon the 26-amino acid signal sequence of precursor cystatin C. In contrast, they found that the A25T (haplotype B) variant of cystatin C was associated principally with mitochondria with some diffusion throughout the cytoplasm and nucleus (but not nucleoli). Ratnayaka et al. (2007) created an artificial mutant A25S precursor cystatin C to elucidate the cause of intracellular mislocalization of the biochemically related variant B (A25T) precursor cystatin C to the mitochondria. A25S precursor cystatin C showed a dual distribution to the Golgi apparatus and to the mitochondria. Furthermore, the level of secretion of A25S cystatin C by RPE cells was intermediary between the wildtype and the ARMD-associated cystatin C. Ratnayaka et al. (2007) stated that their findings further supported the hypothesis that substitution of the ala25 residue with a less hydrophobic residue such as threonine or serine was sufficient to impair the intracellular trafficking and processing of the protein.