Genomic organization and protein sequence of human glutathione reductase. (A) Genomic organization (based on NCBI GenBank entry NC_000008.9[30655977-30704985]) of the glutathione reductase gene GSR located at 8p21.1. Thirteen exons (shown as vertical bars) are separated by large introns. (B) Structure of the exons (boxes) and introns affected by the mutation found in patients 1a and 1b. The deletion of 2246 nucleotides removes not only exons 12 and 13 but also the appropriate signal required for proper splicing of the exon 11–intron 11 boundary, leading to a truncated protein with an aberrant sequence at its C-terminus. The deleted part is flanked on either side by an attacaggca sequence. One of these is part of the deletion. (C) Alignment of the normal (cytosolic) human GR protein sequence (NP_000628) and the mutated sequence found in patient 1. The redox-active site motif CVNVGC is underlined. The aberrant sequence resulting from the deletion of the 2246 nucleotides is highlighted in bold. The residues 287 (T) and 330 (G), which are affected in patient 2 (allele 1 Trp287Stop, allele 2 Gly330Ala), are highlighted in bold in the normal sequence. Indicated above the sequences is the respective protein domain.