Macular Degeneration, Age-Related, 11

A number sign (#) is used with this entry because of evidence that susceptibility to exudative age-related macular degeneration-11 (ARMD11) is conferred by variation in the CST3 gene (604312), which encodes cystatin C, on chromosome 20p11.

For a phenotypic description and a discussion of genetic heterogeneity of age-related macular degeneration, see 603075.

Molecular Genetics

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.

Butler et al. (2015) performed a case-control analysis of the CST3 A25T variant in 350 Caucasian British patients with ARMD, using 3,781 exomes from the Exome Sequencing Project as population controls. Although the result was not significant at an alpha level of 0.05, homozygotes (AA) were at greater risk of ARMD than heterozygotes (GA). Combining their data with that of a previously reported association study (Zurdel et al., 2002), the evidence for a recessive effect on ARMD risk was strengthened (odds ratio, 1.89; p = 0.005). Butler et al. (2015) suggested that common variants with a recessive effect account for some of the 'missing heritability' of multifactorial disease, which genomewide association studies may be underpowered to detect.

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.