Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy

PLoS Genet. 2014 May 1;10(5):e1004320. doi: 10.1371/journal.pgen.1004320. eCollection 2014 May.


Many eukaryotic cell-surface proteins are anchored to the membrane via glycosylphosphatidylinositol (GPI). There are at least 26 genes involved in biosynthesis and remodeling of GPI anchors. Hypomorphic coding mutations in seven of these genes have been reported to cause decreased expression of GPI anchored proteins (GPI-APs) on the cell surface and to cause autosomal-recessive forms of intellectual disability (ARID). We performed homozygosity mapping and exome sequencing in a family with encephalopathy and non-specific ARID and identified a homozygous 3 bp deletion (p.Leu197del) in the GPI remodeling gene PGAP1. PGAP1 was not described in association with a human phenotype before. PGAP1 is a deacylase that removes an acyl-chain from the inositol of GPI anchors in the endoplasmic reticulum immediately after attachment of GPI to proteins. In silico prediction and molecular modeling strongly suggested a pathogenic effect of the identified deletion. The expression levels of GPI-APs on B lymphoblastoid cells derived from an affected person were normal. However, when those cells were incubated with phosphatidylinositol-specific phospholipase C (PI-PLC), GPI-APs were cleaved and released from B lymphoblastoid cells from healthy individuals whereas GPI-APs on the cells from the affected person were totally resistant. Transfection with wild type PGAP1 cDNA restored the PI-PLC sensitivity. These results indicate that GPI-APs were expressed with abnormal GPI structure due to a null mutation in the remodeling gene PGAP1. Our results add PGAP1 to the growing list of GPI abnormalities and indicate that not only the cell surface expression levels of GPI-APs but also the fine structure of GPI-anchors is important for the normal neurological development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Diseases / genetics*
  • DNA, Complementary
  • Female
  • Flow Cytometry
  • Glycosylphosphatidylinositols / metabolism*
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Membrane Proteins / genetics*
  • Mutation*
  • Pedigree
  • Phosphoinositide Phospholipase C / metabolism
  • Phosphoric Monoester Hydrolases / genetics*


  • DNA, Complementary
  • Glycosylphosphatidylinositols
  • Membrane Proteins
  • PGAP1 protein, human
  • Phosphoric Monoester Hydrolases
  • Phosphoinositide Phospholipase C

Grants and funding

This study was supported by the German Intellectual disability Network (MRNET) through a grant from the German Ministry of Research and Education to AR (01GS08160 and 01GR0804-4), by the Deutsche Forschungsgemeinschaft (DFG) through a grant to RAJ (AB393/2-1), by the Deutscher Akademischer Austauschdienst (DAAD) through a scholarship to HT, by Deutsche Forschungsgemeinschaft and Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) within the funding programe Open Access Publishing, by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (a Grant-in-Aid for Scientific Research C 23590363 and a Grant-in-Aid for Scientific Research on Innovative Areas, Exploring molecular basis for brain diseases based on personal genomics 25129705), and from the Takeda Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.