Ether lipid biosynthesis: alkyl-dihydroxyacetonephosphate synthase proteindeficiency leads to reduced dihydroxyacetonephosphate acyltransferase activities

Recent studies have indicated that two peroxisomal enzymes involved in ethe r lipid synthesis, i.e., dihydroxyacetonephosphate acyltransferase and alky l-dihydroxyacetonephosphate synthase, are directed to peroxisomes by differ ent targeting signals, i.e., peroxisomal targeting signal type 1 and type 2 , respectively. In this study, we describe a new human fibroblast cell line in which alkyl-dihydroxyacetonephosphate synthase was found to be deficien t both at the level of enzyme activity and enzyme protein, At the cDNA leve l, a 128 base pair deletion was found leading to a premature stop. Remarkab ly, dihydroxyacetonephosphate acyltransferase activity was strongly reduced to a level comparable to the activities measured in fibroblasts from patie nts affected by the classical form of rhizomelic chondrodysplasia punctata (caused by a defect in peroxisomal targeting signal type 2 import). Dihydro xyacetonephosphate acyltransferase activity was completely normal in anothe r alkyl-dihydroxyacetonephosphate synthase activity-deficient patient. Fibr oblasts From this patient showed normal levels of the synthase protein and inactivity results from a point mutation leading to an amino acid substitut ion. These results strongly suggest that the activity of dihy droxyacetonep hosphate acyltransferase is dependent on the presence of alkyl-dihydroxyace tonephosphate synthase protein, This interpretation implies that the defici ency of dihydroxyacetonephosphate acyltransferase (targeted by a peroxisoma l targeting signal type 1) in the classic form of rhizomelic chondrodysplas ia punctata is a consequence of the absence of the alkyl-dihydroxyacetoneph osphate synthase protein (targeted by a peroxisomal targeting signal the 2) .