At sequencing of the human cystatin C gene 25 years ago, we discovered four quite abundant sequence alterations in the upstream region of the gene. They seem coupled and define a B allele of the CST3 gene. Investigation of a small Caucasian population showed that the frequencey of the B allele was 0.29. Later studies in larger DNA materials of different origin (mostly European) have confiremed a B-allele frequency of 0.25-0.30, meaning that 5-8% of such populations are homozygous for B-allele cystatin C. Three of the alterations reside in segements that should be critical parts of the promoter of the gene, whereas the fourth is in the coding seqence and results in an amino acid alteration Ala->Ser in the penulimate position of the normal 26-residue signal peptide, that is cleaved of from the 146 aa pre-cystatin C upon transport to the ER lumen. Any of the alterations could thus theoretically affect the rate of expression of the gene, or possibly the rate of secretion of the protein following translation. In the original report we compared blood levels of cystatin C in a few healthy individuals homozygous for the most common A allele with a few homozygous for the B allele of CST3, but could not see any clear differences in secreted levels.
The B allele of CST3 have since been studied at the genomic level in clinical materials, and correlations have been seen in different Alzheimer's disease (AD) populations, in age-related macular degeneration (AMD) and in amyotrophic lateral sclerosis (ALS). This has resulted in a renewed interest in possible biomedical consequences of the B-allele variations and prompted us to critically review published results of relevance the past decades as well as to re-analyze our own unpublished results from genomic studies of CST3.