Identification of a fatty acid Delta(6)-desaturase deficiency in human skin fibroblasts

Polyunsaturated fatty acid (PUFA) utilization was investigated in skin fibr oblasts cultured from a female patient with an inherited abnormality in lip id metabolism. These deficient human skin fibroblasts (DF) converted 85-95% less [1-C-14]linoleic acid (18:2n-6) to arachidonic acid (20:4n-6), 95% le ss [3-C-14] tetracosatetraenoic acid (24:4n-6) to docosapentaenoic acid (22 :5n-6), and 95% less [1-C-14]linolenic acid (18:3n-3) and [3-C-14]tetracosa pentaenoic acid (24:5n-3) to docosahexaenoic acid (22:6n-3) than did normal human skin fibroblasts (NF), The only product formed by the DF cultures fr om [1-C-14]tetradecadienoic acid (14:2n-6) was 18:2n-6, However, they produ ced 50-90% as much 20:4n-6 as the NF cultures from [1-C-14]hexadecatrienoic acid (16:3n-6), [1-C-14]gamma -linolenic acid (18:3n-6), and [1-C-14]dihom o-gamma -linolenic acid (20:3n-6), PUFA substrates that contain Delta (6) d ouble bonds. DF also contained 80% more 18:2n-6 and 25% less 20:4n-6, These results suggested that DF are deficient in Delta (6) desaturation, This wa s confirmed by Northern blots demonstrating an 81-94% decrease in Delta (6) -desaturase mRNA content in the DF cultures, whereas the Delta (5)-desatura se mRNA content was reduced by only 14%. This is the first inherited abnorm ality in human PUFA metabolism shown to be associated with a Delta (6)-desa turase deficiency. Furthermore, the finding that the 18- and 24-carbon subs trates are equally affected suggests that a single enzyme carries out both Delta (6) desaturation reactions in human PUFA metabolism.