Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental Retardation Syndrome

Hum Mutat. 2016 Aug;37(8):737-44. doi: 10.1002/humu.23006. Epub 2016 May 19.


HPMRS or Mabry syndrome is a heterogeneous glycosylphosphatidylinositol (GPI) anchor deficiency that is caused by an impairment of synthesis or maturation of the GPI-anchor. The expressivity of the clinical features in HPMRS varies from severe syndromic forms with multiple organ malformations to mild nonsyndromic intellectual disability. In about half of the patients with the clinical diagnosis of HPMRS, pathogenic mutations can be identified in the coding region in one of the six genes, one among them is PGAP3. In this work, we describe a screening approach with sequence specific baits for transcripts of genes of the GPI pathway that allows the detection of functionally relevant mutations also including introns and the 5' and 3' UTR. By this means, we also identified pathogenic noncoding mutations, which increases the diagnostic yield for HPMRS on the basis of intellectual disability and elevated serum alkaline phosphatase. In eight affected individuals from different ethnicities, we found seven novel pathogenic mutations in PGAP3. Besides five missense mutations, we identified an intronic mutation, c.558-10G>A, that causes an aberrant splice product and a mutation in the 3'UTR, c.*559C>T, that is associated with substantially lower mRNA levels. We show that our novel screening approach is a useful rapid detection tool for alterations in genes coding for key components of the GPI pathway.

Keywords: Mabry syndrome; PGAP3; hyperphosphatasia with mental retardation; intellectual disability; noncoding mutations.

MeSH terms

  • 3' Untranslated Regions
  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology*
  • Adolescent
  • Adult
  • Carboxylic Ester Hydrolases
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology*
  • Introns
  • Male
  • Mutation, Missense*
  • Pedigree
  • Phosphorus Metabolism Disorders / genetics*
  • Phosphorus Metabolism Disorders / pathology*
  • Polymorphism, Single Nucleotide*
  • RNA, Messenger / genetics*
  • Receptors, Cell Surface / genetics*
  • Sequence Analysis, DNA / methods
  • Young Adult


  • 3' Untranslated Regions
  • RNA, Messenger
  • Receptors, Cell Surface
  • Carboxylic Ester Hydrolases
  • PGAP3 protein, human

Supplementary concepts

  • Hyperphosphatasia with Mental Retardation