The human GPI1 gene is required for efficient glycosylphosphatidylinositolbiosynthesis

The first step in glycosylphosphatidylinositol (GPI) membrane anchor biosyn thesis that is defective in paroxysmal nocturnal haemoglobinuria is mediate d by an N-acetylglucosaminyl transferase expressed in the endoplasmic retic ulum. Six human genes encode subunits of this enzyme, namely PIG-A, PIG-C, PIG-H, PIG-P, GPI1, and DPM2. Here, the human GPI1 gene is characterised. T his gene is organised into eleven exons. The locus was mapped to chromosome 16p13.3 near the haemoglobin a chain locus. GPI1 is expressed ubiquitously in human cells and tissues. Expression levels are markedly elevated in hae matopoietic tissues (bone marrow, foetal liver). To determine whether human GPI1 is essential for human GPI biosynthesis, antisense RNA was expressed in HEK293 cells. Transfectants exhibited a marked but incomplete decrease i n the expression of a GPI-linked reporter protein, confirming that GPI1 is required for efficient GPI biosynthesis. In contrast, expression of GPI-lin ked proteins is normal in lymphatic cell lines from individuals with the a thalassaemia/mental retardation syndrome, which is characterised by large d eletions from chromosome 16p removing one of the two GPI1 alleles along wit h the haemoglobin a locus. In conclusion, GPI1 plays an important role in t he biosynthesis of GPI intermediates. Due to its autosomal localisation, th e heterozygous deletion of GPI1 does not lead to an overt defect in the exp ression of GPI-linked proteins. (C) 2001 Elsevier Science B.V. All rights r eserved.