Human CCS gene: genomic organization and exclusion as a candidate for amyotrophic lateral sclerosis (ALS)

We have characterized the genomic organization of CCS and determined exon-intron boundaries. The 823 bp coding region of the CCS is organized in 8 exons. We have evaluated involvement of the CCS in ALS by sequencing the entire coding region for mutations in 20 sporadic ALS patients.No causative mutations for the ALS have been detected in the CCS gene in 20 sporadic ALS patients analyzed, but an intragenic single nucleotide polymorphism has been identified.Copper serves as a cofactor for a number of oxygen-processing enzymes involved in diverse metabolic processes, but the metal is highly toxic as a free ion. Upon entering the cell the copper is bound to a number of copper chelating transporters (copper chaperones), which guide the copper ion to different cellular locations while protecting the cellular environment from the toxic effect of copper. Copper chaperones are highly specific for their targets and they participate directly in the loading of the metal into the recipient molecule. One of the copper chaperones is CCS (Copper Chaperone for SOD), which targets copper to Cu, Zn-superoxide dismutase (SOD1) [1].Superoxide dismutases are the major antioxidant enzymes involved in free radical scavenging. These enzymes exist in three distinct forms, where two of them contain copper (SOD1 and SOD3), and the third one contains manganese (SOD2). SOD1 (Cu, Zn-superoxide dismutase) is located in the cytoplasm and peroxisomes, and the metal is inserted into the enzyme in the cytosol by means of the chaperone CCS after the enzyme has been synthesized [1].The CCS gene has been localized to 11q13 and three functional domains have been described in the 274 amino acid long protein product [2,3]. Domain I (1–85) is the copper binding site with the consensus MTCXXC motif that is conserved in several other copper binding proteins including HAH1, ATP7A/ATP7B and SOD1. This domain is important in scavenging Cu from the cells and accepting the metal from the transporters. Domain II (86