Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation

Am J Hum Genet. 2012 Jul 13;91(1):146-51. doi: 10.1016/j.ajhg.2012.05.004. Epub 2012 Jun 7.


Hyperphosphatasia with mental retardation syndrome (HPMRS), an autosomal-recessive form of intellectual disability characterized by facial dysmorphism, seizures, brachytelephalangy, and persistent elevated serum alkaline phosphatase (hyperphosphatasia), was recently shown to be caused by mutations in PIGV, a member of the glycosylphosphatidylinositol (GPI)-anchor-synthesis pathway. However, not all individuals with HPMRS harbor mutations in this gene. By exome sequencing, we detected compound-heterozygous mutations in PIGO, a gene coding for a membrane protein of the same molecular pathway, in two siblings with HPMRS, and we then found by Sanger sequencing further mutations in another affected individual; these mutations cosegregated in the investigated families. The mutant transcripts are aberrantly spliced, decrease the membrane stability of the protein, or impair enzyme function such that GPI-anchor synthesis is affected and the level of GPI-anchored substrates localized at the cell surface is reduced. Our data identify PIGO as the second gene associated with HPMRS and suggest that a deficiency in GPI-anchor synthesis is the underlying molecular pathomechanism of HPMRS.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alkaline Phosphatase / blood*
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Infant
  • Intellectual Disability / genetics*
  • Membrane Proteins / genetics*
  • Models, Molecular
  • Mutation*
  • Pedigree
  • Syndrome


  • Membrane Proteins
  • PIGO protein, human
  • Alkaline Phosphatase