Etherphospholipid biosynthesis and dihydroxyactetone-phosphate acyltransferase: resolution of the genomic organization of the human gnpat gene and its use in the identification of novel mutations

Etherphospholipids are characterised by the occurrence of an alkyl- or alkenyl-group at the sn-1 position of the glycerol backbone. Peroxisomes play an essential role in the formation of etherphospholipids since the first two enzymes of the biosynthetic pathway are strictly peroxisomal. The function of plasmalogens is still an enigma but the recent identification of patients suffering from an isolated defect in either dihydroxyacetone phosphate acyltransferase (GNPAT) or alkyldihydroxyacetone phosphate synthase provides conclusive evidence that plasmalogens play an essential role for human survival and functioning. In this paper we report the complete genomic organisation of the GNPAT gene coding for the peroxisomal dihydroxyacetone phosphate acyltransferase. The gene is located on chromosome 1q42.12-43. It spans approximately 28 kb and consists of 16 exons and 15 introns. This information was used to analyse the GNPAT gene in 12 patients with GNPAT deficiency. All patients analysed were found to have mutations in their GNPAT gene. Of the 9 different mutations found, 2 were missense mutations, 2 small deletions, 1 insertion and 3 mutations were within splice donor/acceptor-sites. Another mutation created an alternative splice donor-site causing the partial deletion of an exon. The data obtained provide conclusive evidence for the major role of GNPAT in etherphospholipid biosynthesis.