Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes

Abstract

Background: Defects in the glycosylphosphatidylinositol (GPI) biosynthesis pathway can result in a group of congenital disorders of glycosylation known as the inherited GPI deficiencies (IGDs). To date, defects in 22 of the 29 genes in the GPI biosynthesis pathway have been identified in IGDs. The early phase of the biosynthetic pathway assembles the GPI anchor (Synthesis stage) and the late phase transfers the GPI anchor to a nascent peptide in the endoplasmic reticulum (ER) (Transamidase stage), stabilizes the anchor in the ER membrane using fatty acid remodeling and then traffics the GPI-anchored protein to the cell surface (Remodeling stage).

Results: We addressed the hypothesis that disease-associated variants in either the Synthesis stage or Transamidase+Remodeling-stage GPI pathway genes have distinct phenotypic spectra. We reviewed clinical data from 58 publications describing 152 individual patients and encoded the phenotypic information using the Human Phenotype Ontology (HPO). We showed statistically significant differences between the Synthesis and Transamidase+Remodeling Groups in the frequencies of phenotypes in the musculoskeletal system, cleft palate, nose phenotypes, and cognitive disability. Finally, we hypothesized that phenotypic defects in the IGDs are likely to be at least partially related to defective GPI anchoring of their target proteins. Twenty-two of one hundred forty-two proteins that receive a GPI anchor are associated with one or more Mendelian diseases and 12 show some phenotypic overlap with the IGDs, represented by 34 HPO terms. Interestingly, GPC3 and GPC6, members of the glypican family of heparan sulfate proteoglycans bound to the plasma membrane through a covalent GPI linkage, are associated with 25 of these phenotypic abnormalities.

Conclusions: IGDs associated with Synthesis and Transamidase+Remodeling stages of the GPI biosynthesis pathway have significantly different phenotypic spectra. GPC2 and GPC6 genes may represent a GPI target of general disruption to the GPI biosynthesis pathway that contributes to the phenotypes of some IGDs.

Keywords: Congenital disorders of glycosylation; GPI-anchor; Glycosylphosphatidylinositols; Human phenotype ontology.

Fig. 1

GPI biosynthesis pathway. Illustrated is the biosynthetic pathway of GPI-AP. In the Synthesis-stage, twenty genes are responsible for synthesizing the GPI anchor (Synthesis Group, genes highlighted in red). The Transamidase+Remodelinglate-stage couples the protein to the GPI anchor and mediates trafficking through the Golgi apparatus to the cell surface (Tranasmidase+Remodeling Group, genes highlighted in blue) [–6]. Abbreviations: PI: phosphatidylinositol; EtNP: ethanolamine phosphate; GlcN: D-Glucosamine; GlcNAc: N-Acetyl-D-glucosamine; E.R.:endoplasmic reticulum. Gene symbols: See Tables 1 and 2

Fig. 2

Example of HPO hierarchy. The hierarchy in the HPO for cleft palate and neighboring phenotypes

Fig. 3

Schematic representation of FGFR2 signaling through the Ras/Raf/MAPK pathway. FGFR2 and B-Raf were found 2 associated with 15 of 16 phenotypes over-represented in the Transamidase+Remodeling Group and are in signaling cascades associated with lipid rafts which contain GPI-anchored proteins. *Numerous FGFs activate the FGFR2. Only FGF2 is known to be associated with lipid rafts (purple) [–58]